Glutamate receptor antagonists

ABSTRACT

The present invention is a compound of formula                  
 
wherein
     X is an ethynediyl group, R 1 , R 2  and R 3  are as defined in the specification.

PRIORITY TO RELATED APPLICATIONS

This application is a Division of Ser. No. 10/300,449, filed Nov. 20,2002, which is now U.S. Pat. No. 6,960,578, which is a Division of Ser.No. 09/687,241, filed Oct. 13, 2000, which is now U.S. Pat. No.6,509,328, issued: Jan. 21, 2003.

BACKGROUND OF THE INVENTION

In the central nervous system (CNS) the transmission of stimuli takesplace by the interaction of a neurotransmitter, which is sent out by aneuron, with a neuroreceptor.

L-glutamic acid, the most commonly occurring neurotransmitter in theCNS, plays a critical role in a large number of physiological processes.The glutamate-dependent stimulus receptors are divided into two maingroups. The first main group forms ligand-controlled ion channels. Themetabotropic glutamate receptors (mGluR) form the second main group and,furthermore, belong to the family of G-protein-coupled receptors.

At present, eight different members of these mGluR are known and ofthese some even have sub-types. On the basis of structural parameters,the different influences on the synthesis of secondary metabolites andthe different affinity to low-molecular weight chemical compounds, theseeight receptors can be subdivided into three sub-groups: mGluR1 andmGluR5 belong to group I, mGluR2 and mGluR3 belong to group II andmGluR4, mGluR6, mGluR7 and mGluR8 belong to group III.

Ligands of metabotropic glutamate receptors belonging to the group IIcan be used for the treatment or prevention of acute and/or chronicneurological disorders such as psychosis, schizophrenia, Alzheimer'sdisease, cognitive disorders and memory deficits.

SUMMARY OF THE INVENTION

The present invention relates to compounds of the general formula I:

These compounds have been discovered to act as metabotropic glutamatereceptor antagonists and accordingly are useful for the treatment of arange of neurological disorders, including psychosis, schizophrenia,Alzheimer's and other cognitive and memory disorders.

Objects of the present invention are compounds of formula I and theirpharmaceutically acceptable salts per se and as pharmaceutically activesubstances, their manufacture, medicaments based on one or morecompounds in accordance with the invention and their production, as wellas the use of the compounds in accordance with the invention in thecontrol or prevention of neurological disorders, and, respectively, forthe production of corresponding medicaments.

DETAILED DESCRIPTION

The present invention relates to compounds of formula I

wherein

-   X is a single bond or an ethynediyl group, wherein,-   in case X is a single bond,-   in case X is an ethynediyl group,

R¹ is hydrogen; lower alkyl, optionally substituted with hydroxy;halo-lower alkyl; lower cycloalkyl, optionally substituted with hydroxy,lower alkyl, halo-lower alkyl, lower alkoxy, halo-lower alkoxy, orhalogen; lower cycloalkenyl, optionally substituted with lower alkyl,halo-lower alkyl, lower alkoxy, halo-lower alkoxy, halogen, or oxo;lower alkenyl; phenyl, optionally substituted with halogen, lower alkyl,halo-lower alkyl, lower cycloalkyl, lower alkoxy, halo; 5 or 6 memberedheterocyclic ring, optionally substituted with lower alkyl, halogen,oxo, benzyloxy, benzoyl, methanesulfonyl, benzenesulfonyl, acetyl,pivaloyl, tert. butoxycarbonyl, or tert. butylcarbonyl; or benzofuranyl;

R³ is phenyl; pyridine; thiophenyl or thiazolyl, which are optionallysubstituted with halogen, cyano, nitro, azido, hydroxy, carboxy,morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl,trimethylsilyl-ethynyl, or from lower alkyl, lower alkynyl, loweralkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, loweralkylaminocarbonyl, which are optionally substituted by amino, loweralkylamino, acylamino, oxo, hydroxy; lower alkoxy, lower alkylthio, orcarboxy which is optionally esterified or amidated; or a 5-memberedaromatic heterocycle which is optionally substituted by amino, loweralkylamino, acylamino, oxo, hydroxy, lower alkoxy, lower alkylthio,carboxy which is optionally esterified with lower alkyl or amidated withlower alkylamino which is eventually substituted by hydroxy, or loweralkyl which is optionally substituted by halogen, hydroxy, amino, loweralkylamino, acylamino, or amidino, which is optionally substituted bylower alkyl, —C(NRR′)═NR″ (where R, R′ and R″ are hydrogen or loweralkyl), hydroxy, lower alkoxy, lower alkylthio, acyloxy, loweralkylsulfinyl, lower alkylsulfonyl, lower alkoxy-lower alkylsulfanyl,lower alkylsulfanyl, cycloalkylsulfinyl, cycloalkylsulfonyl,hydroxyimino, or lower alkoxyimino, which is optionally esterified oramidated, lower alkenyl, oxo, cyano, carbamoyloxy, or sulfamoyl which isoptionally substituted by lower alkyl,

-   with the proviso that, if X is a single bond and R³ is pyridinyl, R¹    is not hydrogen, or methyl;    and their pharmaceutically acceptable acid addition salts.

It has surprisingly been found that the compounds of formula I aremetabotropic glutamate receptor antagonists. Compounds of formula I aredistinguished by valuable therapeutic properties.

The compounds of the present invention can be used for the treatment orprevention of acute and/or chronic neurological disorders such aspsychosis, schizophrenia, Alzheimer's disease, cognitive disorders andmemory deficits.

Other treatable indications in this connection are restricted brainfunction caused by bypass operations or transplants, poor blood supplyto the brain, spinal cord injuries, head injuries, hypoxia caused bypregnancy, cardiac arrest and hypoglycaemia. Further treatableindications are chronic and acute pain, Huntington's chorea, amyotrophiclateral sclerosis (ALS), dementia caused by AIDS, eye injuries,retinopathy, idiopathic parkinsonism or parkinsonism caused bymedicaments as well as conditions which lead to glutamate-deficiencyfunctions, such as e.g. muscle spasms, convulsions, migraine, urinaryincontinence, nicotine addiction, opiate addiction, anxiety, vomiting,dyskinesia and depressions.

Objects of the present invention are compounds of formula I and theirpharmaceutically acceptable salts per se and as pharmaceutically activesubstances, their manufacture, medicaments based on one or morecompounds in accordance with the invention and their production, as wellas the use of the compounds in accordance with the invention in thecontrol or prevention of illnesses of the aforementioned kind, and,respectively, for the production of corresponding medicaments.

Preferred compounds of formula I are those in which R³ is phenylsubstituted in meta position by cyano; halogen; or imidazolyl, which isoptionally substituted by lower alkyl; or 1,3-thiazolyl which isoptionally substituted by hydroxy-lower alkyl, carboxy, or—CO—NH—(CH₂)₂OH; 1,3-oxazolyl; 1,2,3-triazolyl; 1,2,4-triazolyl which isoptionally substituted with lower alkyl; tetrazolyl; or isoxazolyl,which is optionally substituted by lower alkyl;

The following are examples of such compounds:

-   3-(4-Oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile;-   4-(3-Chloro-phenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   4-(3-Imidazol-1-yl-phenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile;-   8-(4-Fluoro-phenylethynyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   8-(4-Fluoro-phenylethynyl)-4-(3-[1,2,4]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   8-(4-Fluoro-phenyl)-4-[3-(4-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   8-(4-Fluoro-2-methyl-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   8-(4-Fluoro-2-hydroxy-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   8-(4-Fluoro-phenylethynyl)-4-(3-tetrazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   8-(2-Fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   8-(4-Fluoro-phenyl)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   8-(2,4-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   8-(2,3-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   8-(2-Fluoro-phenyl)-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   2-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylic    acid;-   2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-4-methyl-thiazole-5-carboxylic    acid (2-hydroxy-ethyl)-amide; and-   4-[3-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one;

Compounds of formula I, in which R³ is thiophenyl, preferablytiophen-2-yl, optionally substituted with halogen, cyano; or pyridinyl,preferably pyridin-4-yl, optionally substituted, preferably in the2-position, with halogen, or cyano; are also preferred.

The following are examples of such compounds:

-   8-(4-Fluoro-phenylethynyl)-4-(2-imidazol-1-yl-pyridin-4-yl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one;-   2-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]-thiophene-3-carbonitrile;-   4-(4-Oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile;    and-   4-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile.

All tautomeric forms of the compounds of invention are also embracedherewith.

The term “lower alkyl” used in the present description denotesstraight-chain or branched saturated hydrocarbon residues with 1–7carbon atoms, preferably with 1–4 carbon atoms, such as methyl, ethyl,n-propyl, i-propyl and the like.

The term “lower alkynyl” used in the present description denotesstraight-chain or branched unsaturated hydrocarbon residues with 2–7carbon atoms, preferably with 2–4 carbon atoms, such as ethynyl,n-propynyl, and the like.

The term “lower cycloalkyl” used in the present description denotescyclic saturated hydrocarbon residues with 3–5 carbon atoms, preferablywith 3 carbon atoms, such as cyclopropyl.

The term “lower alkoxy” denotes a lower alkyl residue in the sense ofthe foregoing definition bonded via an oxygen atom.

The term “halogen” embraces fluorine, chlorine, bromine and iodine.

The expression “5 or 6 membered heterocyclic ring” embraces thiophene,furane, thiazole, pyridine, partially hydrated pyridine, for example2-pyridone, partially hydrogenated prydine, for exampletetrahydropyridine, five-membered aromatic heterocycle containing up to4 heteroatoms, selected from O, S, N, embracing imidazol-1-yl,imidazol-2-yl, imidazol-4-yl; pyrazol-1-yl, pyrazol-3-yl, pyrazol-4-yl;1,3-thiazol-2-yl, 1,3-thiazol-4-yl, 1,3-thiazol-5-yl; 1,3-oxazol-2-yl,1,3-oxazol-4-yl, 1,3-oxazol-5-yl, 1,2-oxazol-3-yl, 1,2-oxazol-4-yl,1,2-oxazol-5-yl; 1,2,3-triazol-1-yl, 1,2,3-triazol-4-yl,1,2,4-triazol-1-yl, 1,2,4-triazol-3-yl, 1,2,4-triazol-2-yl;1,2,4-oxadiazol-2-yl, 1,2,4-oxadiazol-3-yl, 1,2,4-oxadiazol-5-yl,1,2,3-oxadiazol-4-yl, 1,2,3-oxadiazol-5-yl; 1,2,4-thiadiazol-2-yl,1,2,4-thiadiazol-3-yl, 1,2,4-thiadiazol-5-yl, 1,2,3-thiadiazol-4-yl,1,2,3-thiadiazol-5-yl; tetrazol-1-yl, tetrazol-2-yl, tetrazol-5-yl;

The compounds of formula I and their pharmaceutically acceptable saltscan be manufactured according to the following methods:

Compounds of formula I, in which R¹, R³ and X are as described above canbe prepared according to scheme A, by, for example, cleaving the BOCprotecting group in compounds of formula II, and concomitant cyclizationof the deprotected compound. The deprotection-cyclization step can becarried out by treating the compounds of formula II with a bronstedacid, like for example trifluoroacetic acid (TFA), in an inert solvent,like for example dichloromethane (DCM). The reaction is preferablycarried out at temperatures between 0° C. and 50° C. It may beadvantageous to use also anisole or 1,3-dimethoxybenzene as acarbocation scavenger in the reaction mixture. Any other suitable aminoprotecting group, such as e.g. Fmoc or benzyloxycarbonyl (Z), can bealternatively used instead of the BOC group.

Compounds of formula II, in which R¹, R³ and X are as described above,can be prepared according to scheme B by for example reacting a compoundof formula III with a dioxinone (formula IV) in an inert solvent likefor example toluene or xylene at elevated temperatures, preferablybetween 80° C. and 160° C.

Alternatively, compounds of formula II can also be prepared by forexample reaction of a compound of formula III with a β-ketoester(formula IVa), in which R³ is as described above using the sameconditions as described for the reaction with the dioxinones.

According to scheme C, compounds of formula III in which R¹ is asdescribed above for compounds where X is a single bond can be preparedby different routes from the iodo-compound IX, depending on the natureof R¹. As shown in scheme C, the key steps are coupling reactions ofSuzuki- and Stille-type in presence or absence of carbonmonoxide. Theexact conditions for the respective compounds can be found in theexperimental part.

According to scheme D, the key intermediate iodide IX can be preparedfrom commercially available 2-nitroaniline by a standardiodination-protection sequence.

According to scheme E, compounds of formula IIIa in which R¹ is asdescribed above for compounds where X is an ethynediyl group can beprepared by different routes from the iodo-compound IX, depending on thenature of R¹. As shown in Scheme E, the transformation can for examplebe carried out by directly attaching the R¹-alkynediyl-substituent via aSonogashira-type coupling followed by the reduction of the nitro groupor

b) by two stepwise Sonogashira-type couplings, in which firsttrimethylsilyl-acetylene is coupled to iodide IX to yield, afterdeprotection with sodium hydroxide in methanol, the intermediate XIIwhich then can be transformed via a second Sonogashira-type couplingwith the appropriate reactant R¹—I, R¹—Br or R¹—OSO₂CF₃ and reduction ofthe nitro group to the desired compounds.

The exact conditions for the respective compounds can be found in theexperimental part.

According to Scheme F, the dioxinones and β-keto esters building blockswith the formula IV and IVa can be prepared by methods known to someoneskilled in the art from the corresponding carboxylic acid derivativesR³—COR, i.e. free acids, methyl or ethyl esters and acid chlorides. Theexact conditions for the corresponding compounds can be found in theexperimental part.

Another synthetic route to prepare compounds of formula Ic, in which R¹and X have the meaning as described above and R³ is a phenyl-carboxamideof formula C(O)NR⁴R⁵, in which R⁴ and R⁵ are hydrogen, lower alkyl or R⁴and R⁵ together form a morpholino-residue or a N-methyl-piperazine isoutlined in scheme G:

The exact conditions for the respective compounds can be found in theexperimental part.

Still another way to prepare compounds of formula I is the reaction of4-aryl-8-iodo-1,3-dihydro-benzo[b][1,4]diazepin-2-ones (Formula Id,Synthetic Scheme H) with alkynes of formula R¹—C≡C—, in which R¹ has themeaning as described above, in a Sonogashira-coupling.

The exact conditions for the respective compounds can be found in theexperimental part.

The pharmaceutically acceptable salts can be manufactured readilyaccording to methods known per se and taking into consideration thenature of the compound to be converted into a salt. Inorganic or organicacids such as, for example, hydrochloric acid, hydrobromic acid,sulphuric acid, nitric acid, phosphoric acid or citric acid, formicacid, fumaric acid, maleic acid, acetic acid, succinic acid, tartaricacid, methanesulphonic acid, p-toluenesulphonic acid and the like aresuitable for the formation of pharmaceutically acceptable salts of basiccompounds of formula I.

The compounds of formula I and their pharmaceutically acceptable saltsare metabotropic glutamate receptor antagonists and can be used for thetreatment or prevention of acute and/or chronic neurological disorders,such as psychosis, schizophrenia, Alzheimer's disease, cognitivedisorders and memory deficits. Other treatable indications arerestricted brain function caused by bypass operations or transplants,poor blood supply to the brain, spinal cord injuries, head injuries,hypoxia caused by pregnancy, cardiac arrest and hypoglycaemia. Furthertreatable indications are acute and chronic pain, Huntington's chorea,ALS, dementia caused by AIDS, eye injuries, retinopathy, idiopathicparkinsonism or parkinsonism caused by medicaments as well as conditionswhich lead to glutamate-deficient functions, such as e.g. muscle spasms,convulsions, migraine, urinary incontinence, nicotine addiction,psychoses, opiate addiction, anxiety, vomiting, dyskinesia anddepression.

The compounds of formula I and pharmaceutically acceptable salts thereofcan be used as medicaments, e.g. in the form of pharmaceuticalpreparations. The pharmaceutical preparations can be administeredorally, e.g. in the form of tablets, coated tablets, dragées, hard andsoft gelatin capsules, solutions, emulsions or suspensions. However, theadministration can also be effected rectally, e.g. in the form ofsuppositories, or parenterally, e.g. in the form of injection solutions.

The compounds of formula I and pharmaceutically acceptable salts thereofcan be processed with pharmaceutically inert, inorganic or organiccarriers for the production of pharmaceutical preparations. Lactose,corn starch or derivatives thereof, talc, stearic acid or its salts andthe like can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard gelatin capsules. Suitable carriers for softgelatin capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like; depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatin capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, sucrose, invertsugar, glucose and the like. Adjuvants, such as alcohols, polyols,glycerol, vegetable oils and the like, can be used for aqueous injectionsolutions of water-soluble salts of compounds of formula I, but as arule are not necessary. Suitable carriers for suppositories are, forexample, natural or hardened oils, waxes, fats, semi-liquid or liquidpolyols and the like.

In addition, the pharmaceutical preparations can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They can also contain still othertherapeutically valuable substances.

As mentioned earlier, medicaments containing one or more compounds offormula I or a pharmaceutically acceptable salt thereof and atherapeutically inert excipient are also an object of the presentinvention, as is a process for the production of such medicaments whichcomprises bringing one or more compounds of formula I orpharmaceutically acceptable salts thereof and, if desired, one or moreother therapeutically valuable substances into a galenical dosage formtogether with one or more therapeutically inert carriers.

The dosage can vary within wide limits and will, of course, be fitted tothe individual requirements in each particular case. In general, theeffective dosage for oral or parenteral administration is between0.01–20 mg/kg/day, with a dosage of 0.1–10 mg/kg/day being preferred forall of the indications described. The daily dosage for an adult humanbeing weighing 70 kg accordingly lies between 0.7–1400 mg per day,preferably between 7 and 700 mg per day.

The present invention relates also to the use of compounds of formula Iand of pharmaceutically acceptable salts thereof for the production ofmedicaments, especially for the control or prevention of acute and/orchronic neurological disorders of the aforementioned kind.

The compounds of the present invention are group II mGlu receptorantagonists as determined using the assay described by Cartmell et al.(Br. J. Pharmacol. 1998, 123(3), 497–504).

The compounds show activities, as measured in the assay described below,of 50 μM or less, typically 3 μM or less, and ideally of 0.5 μM or less.In the table below are described some specific pKi values of preferredcompounds

Ki Compound mGlu2 (μM)3-(7-Iodo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2- 0.017yl)-benzonitrile 4-(3-Chloro-phenyl)-8-phenylethynyl-1,3-dihydro- 0.040benzo[b][1,4]diazepin-2-one4-(3-Imidazol-1-yl-phenyl)-8-phenylethynyl-1,3-dihydro- 0.006benzo[b][1,4]diazepin-2-one 3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-0.055 benzo[b][1,4]diazepin-2-yl]-benzonitrile8-(4-Fluoro-phenylethynyl)-4-(3-imidazol-1-yl-phenyl)- 0.0041,3-dihydro-benzo[b][1,4]diazepin-2-one8-(4-Fluoro-phenylethynyl)-4-(3-[1,2,4]triazol-1-yl- 0.049phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one8-(4-Fluoro-phenylethynyl)-4-(2-imidazol-1-yl-pyridin-4- 0.004yl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one8-(4-Fluoro-phenyl)-4-[3-(4-methyl-imidazol-1-yl)- 0.016phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one8-(4-Fluoro-2-methyl-phenyl)-4-(3-imidazol-1-yl-phenyl)- 0.0501,3-dihydro-benzo[b][1,4]diazepin-2-one8-(4-Fluoro-2-hydroxy-phenyl)-4-(3-imidazol-1-yl- 0.170phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one2-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H- 0.250benzo[b][1,4]diazepin-2-yl]-thiophene-3-carbonitrile8-(4-Fluoro-phenylethynyl)-4-(3-tetrazol-1-yl-phenyl)-1,3- 0.036dihydro-benzo[b][1,4]diazepin-2-one4-(4-Oxo-7-phenylethynyl-4,5-dihydro-3H- 0.039benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile4-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H- 0.026benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile8-(2-Fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3- 0.008dihydro-benzo[b][1,4]diazepin-2-one8-(4-Fluoro-phenyl)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]- 0.2891,3-dihydro-benzo[b][1,4]diazepin-2-one8-(2,4-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)- 0.0101,3-dihydro-benzo[b][1,4]diazepin-2-one8-(2-Fluoro-phenyl)-4-(2-imidazol-1-yl-thiazol-4-yl)-1,3- 0.298dihydro-benzo[b][1,4]diazepin-2-one8-(2,3-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)- 0.0131,3-dihydro-benzo[b][1,4]diazepin-2-one8-(2-Fluoro-phenyl)-4-[3-(4-hydroxymethyl-thiazol-2-yl)- 0.016phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one.2-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H- 0.016benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylic acid.2-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H- 0.049benzo[b][1,4]diazepin-2-yl]-phenyl}-4-methyl-thiazole-5- carboxylic acid(2-hydroxy-ethyl)-amide4-[3-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-8-(4- 0.108fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

[³H]-LY354740 Binding on mGlu2 Transfected CHO Cell Membranes

Transfection and Cell Culture

cDNA encoding the rat mGlu2 receptor protein in pBluescript II wasobtained from Prof. S. Nakanishi (Kyoto, Japan), and subcloned into theeukaryotic expression vector pcDNA I-amp from Invitrogen (NV Leek, TheNetherlands). This vector construct (pcD1mGR2) was co-transfected with apsvNeo plasmid encoding the gene for neomycin resistance, into CHO cellsby a modified calcium phosphate method described by Chen & Okayama(1988). The cells were maintained in Dulbecco's Modified Eagle mediumwith reduced L-glutamine (2 mM final concentration) and 10% dialysedfoetal calf serum from Gibco BRL (Basel, Switzerland). Selection wasmade in the presence of G-418 (1000 ug/ml final). Clones were identifiedby reverse transcription of 5 μg total RNA, followed by PCR using mGlu2receptor specific primers 5′-atcactgcttgggtttctggcactg-3′ and5′-agcatcactgtgggtggcataggagc-3′ in 60 mM Tris HCl (pH 10), 15 mM(NH₄)₂SO₄, 2 mM MgCl₂, 25 units/ml Taq Polymerase with 30 cyclesannealing at 60° C. for 1 min., extension at 72° C. for 30 s, and 1 min.95° C. denaturation.

Membrane Preparation

Cells, cultured as above, were harvested and washed three times withcold PBS and frozen at −80° C. The pellet was resuspended in cold 20 mMHEPES-NaOH buffer containing 10 mM EDTA (pH 7.4), and homogenised with apolytron (Kinematica, AG, Littau, Switzerland) for 10 s at 10 000 rpm.After centrifugation for 30 min. at 4° C., the pellet was washed oncewith the same buffer, and once with cold 20 mM HEPES-NaOH buffercontaining 0.1 mM EDTA, (pH 7.4). Protein content was measured using thePierce method (Socochim, Lausanne, Switzerland) using bovine serumalbumin as standard.

[³H]-LY354740 Binding

After thawing, the membranes were resuspended in cold 50 mM Tris-HClbuffer containing 2 mM MgCl₂ and 2 mM CaCl₂, (pH 7) (binding buffer).The final concentration of the membranes in the assays was 25 μgprotein/ml. Inhibition experiments were performed with membranesincubated with 10 nM [³H]-LY354740 at room temperature, for 1 hour, inpresence of various concentrations of the compound to be tested.Following the incubations, membranes were filtered onto Whatmann GF/Cglass fiber filters and washed 5 times with cold binding buffer. Nonspecific binding was measured in the presence of 10 μM DCG IV (TOCRISNo. 0975). After transfer of the filters into plastic vials containing10 ml of Ultima-gold scintillation fluid (Packard, Zürich, Switzerland),the radioactivity was measured by liquid scintillation in a Tri-Carb2500 TR counter (Packard, Zürich, Switzerland).

Data Analysis.

The inhibition curves were fitted with a four parameter logisticequation giving IC50 values, and Hill coefficients.

EXAMPLES

General Procedure A (Synthetic Scheme D):

Preparation of (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl estersfrom 4-iodo-2-nitroanilines.

Method a

To a solution of diphosgene (4.1 mL, 34.1 mmol) in EtOAc (40 mL) at 0°C. was added a solution of the 4-iodo-2-nitroaniline (45.5 mmol) inEtOAc (200–500 mL), and the mixture was heated to reflux for 18 h. Thesolvent was removed in vacuum to leave a brown solid, which wastriturated with hot hexane (200 mL). The solid material was filtered offand the filtrate was concentrated under reduced pressure to leave thepure 4-iodo-2-nitrophenylisocyanate as a yellow solid. This material wasrefluxed in a mixture of excess tert.-BuOH in CH₂Cl₂ for 2.5 h. Removalof the solvent left an orange solid which was purified by silica gelcolumn chromatography with hexane/EtOAc to give the(4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester as a yellowsolid.

Method b

To a mixture of the 4-iodo-2-nitroaniline (142 mmol) and cesiumcarbonate (55.5 g, 170 mmol) in 2-butanone (740 mL) was dropwise added asolution of Boc₂O (37.8 g, 173 mmol) in 2-butanone (170 mL) and theresulting mixture was stirred at 52° C. for 26 h. The solvent wasremoved in vacuum, the residue was treated with a mixture of H₂O (240mL) and MeOH (240 mL) and extracted with hexane (3×500 mL). The combinedhexane layer was washed with brine (200 mL) and all aqueous layers werereextracted with hexane (300 mL). All combined hexane layers were driedover MgSO₄, filtered and the solvent was removed in vacuum to give anorange solid, which was purified by silica gel column chromatographywith hexane/EtOAc to give the (4-iodo-2-nitro-phenyl)-carbamic acidtert.-butyl ester as a yellow solid.

Method c

To a solution of the 4-iodo-2-nitroaniline (550 mmol) and DMAP (1.22 g,10 mmol) in THF (1000 mL) at 23° C. was dropwise added within 70 min asolution of Boc₂O (246 g, 1128 mmol) in THF (500 mL) and stirring wascontinued at 23° C. for 75 min. The entire mixture was evaporated todryness and dried at HV to leave a dark brown solid (253.59 g). Thismaterial was dissolved in DCM (1100 mL), cooled to 0° C. and TFA (84 mL,1100 mmol) was added dropwise. The mixture was stirred at 0° C. for 2 h,poured into icecold sat. NaHCO3-sol., extracted with DCM, washed withbrine and dried over MgSO₄. Removal of the solvent in vacuum left a darkbrown solid (199.71 g) which was coated on silica gel and purified bysilica gel column chromatography with hexane/EtOAc to give the(4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester as a yellowsolid.

Example A1 (4-Iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester

Prepared the isocyanate from 4-iodo-2-nitroaniline (12.0 g, 45.5 mmol;prepared from 2-nitroaniline according to Wilson, J. Gerald; Hunt,Frederick C. Aust. J. Chem. 1983, 36, 2317–25; CAS-No. [20691-72-9])with diphosgene (4.1 mL, 34.1 mmol) in EtOAc (250 mL), followed bytreatment with tert.-BuOH (12 mL) in CH₂Cl₂ (60 mL) according to thegeneral procedure A (method a). Obtained as a yellow solid (8.23 g,82%). MS (EI) 390 (M⁺); mp 92–94° C.

Example A2 (4-Isopropyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester

Prepared from 4-isopropyl-2-nitroaniline (CAS-No. [63649-64-9]) byreaction with Boc₂O and cat. DMAP in THF, followed by treatment with TFAin CH₂Cl₂ according to the general procedure A (method c). Obtained as ayellow oil (14.1 g).

MS (EI) 280 (M⁺).

Example A3 (4-Cyclopropyl-2-nitro-phenyl)-carbamic acid tert.-butylester

Prepared from 4-cyclopropyl-2-nitro-phenylamine prepared from nitrationof N-(4-cyclopropyl-phenyl)-acetamide (CAS-No. [63649-64-9] with 65%HNO₃ in Ac₂O and subsequent saponification with 6N NaOH in refluxingdioxane) by reaction with Boc₂O and cat. DMAP in THF, followed bytreatment with TFA in CH₂Cl₂ according to the general procedure A(method c). Obtained as an orange liquid (2.33 g).

MS (EI) 278 (M⁺).

General Procedure B (Synthetic Scheme C)

Preparation of (4-aryl-2-nitro-phenyl)-carbamic acid tert.-butyl estersby direct Suzuki-coupling of (4-iodo-2-nitro-phenyl)-carbamic acidtert.-butyl esters with arylboronic acids.

A mixture of the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(3.0 mmol), the arylboronic acid (4.5 mmol) and PdCl₂(PPh₃)₂ (2 mol %)was refluxed in 1,4-dioxane (25 mL) and 2M Na₂CO₃-sol. (7.5 mL) [oralternatively with 1M NaHCO₃-sol. (7.5 mL), LiCl (6.0 mmol) and(Ph₃P)₄Pd (3 mol %) in DME (30 mL); also possible with Et₃N (9.0 mmol),Pd(OAc)₂ (3 mol %), PPh₃ (6 mol %) in DMF (10 mL) at 100° C.] until tlcindicated complete conversion of the iodide. The mixture was transferredinto a separating funnel, H₂O (25 mL) was added and the product wasextracted with ether or EtOAc (3×30 mL). The combined organic layerswere washed with brine (50 mL) and dried over Na₂SO₄. Removal of thesolvent left a brown residue, which was purified by silica gel columnchromatography with cyclohexane/ether or cyclohexane/EtOAc to give thetitle compound.

Example B1 (4′-Methoxy-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 4-methoxyphenylboronic acid according to the generalprocedure B. Obtained as a yellow solid (637 mg).

MS (ISN) 343 [(M−H)⁻]; mp 107–109° C.

Example B2 (2-Nitro-4-thiophen-3-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 3-thiopheneboronic acid according to the generalprocedure B. Obtained as a yellow solid (326 mg).

MS (ISN) 319 [(M−H)⁻].

Example B3 (4-Furan-2-yl-2-nitro-phenyl)-carbamic acid tert.-butyl ester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and furan-2-boronic acid according to the general procedureB. Obtained as an orange solid (282 mg).

MS (EI) 304 (M⁺); mp 169–172° C.

Example B4 (4′-Ethyl-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 4-ethylbenzene boronic acid according to the generalprocedure B. Obtained as an orange solid (689 mg).

MS (EI) 343 [(M+H)⁺]; mp 94–99° C.

Example B5 (3-Nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) (994 mg, 2.73 mmol) and phenyl boronic acid (576 mg, 3.00mmol) according to the general procedure B. Obtained as a bright yellowsolid (800 mg).

MS (EI) 314 (M⁺); mp 119–121° C.

Example B6 (4-Furan-3-yl-2-nitro-phenyl)-carbamic acid tert.-butylester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and furan-3-boronic acid according to the general procedureB. Obtained as an orange solid (855 mg).

MS (ISP) 322 [(M+NH₄)⁺] and 327 [(M+Na)⁺]; mp 105–110° C.

Example B7 (4-Naphthalen-1-yl-2-nitro-phenyl)-carbamic acid tert.-butylester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 1-naphthylboronic acid according to the generalprocedure B. Obtained as a yellow foam (1.0 g).

MS (ISN) 363 [(M−H)⁻]; mp 60–66° C.

Example B8 (3′-Methoxy-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 3-methoxyphenylboronic acid according to the generalprocedure B. Obtained as an orange solid (818 mg).

MS (ISP) 345 [(M+H)⁺], 362 [(M+NH₄)⁺] and 367 [(M+Na)⁺]; mp 104–107° C.

Example B9 (3-Nitro-4′-trifluoromethoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 4-(trifluoromethoxy)benzene boronic acid according tothe general procedure B. Obtained as an orange solid (569 mg).

MS (ISN) 397 [(M−H)⁻]; mp 145–147° C.

Example B10 (2′-Fluoro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 2-fluorobenzene boronic acid according to the generalprocedure B. Obtained as a yellow solid (1.48 g).

MS (ISN) 331 [(M−H)⁻]; mp 131–133° C.

Example B11 (3′-Fluoro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 3-fluorobenzene boronic acid according to the generalprocedure B. Obtained as a yellow solid (3.87 g).

MS (ISN) 331 [(M−H)⁻]; mp 93–96° C.

Example B12 (4′-Fluoro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 4-fluorobenzene boronic acid according to the generalprocedure B. Obtained as a yellow solid (1.08 g).

MS (ISN) 331 [(M−H)⁻]; mp 155–167° C.

Example B13 (4′-Fluoro-2′-methyl-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 4-fluoro-2-methylbenzene boronic acid [CAS-no.139911-29-8; prepared from 2-bromo-5-fluorotoluene by reaction withn-BuLi at −78° C. followed by treatment with B(OMe)₃ and subsequenthydrolysis] according to the general procedure B. Obtained as a yellowsolid (1.71 g).

MS (EI) 346 (M⁺).

Example B14 (4′-Fluoro-2′-methoxymethoxy-3-nitro-biphenyl-4-yl)-carbamicacid tert.-butyl ester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 4-fluoro-2-methoxymethoxybenzene boronic acid [preparedfrom 1-bromo-4-fluoro-2-(methoxymethoxy)benzene (CAS-no. 162269-78-5) byreaction with n-BuLi at −78° C. followed by treatment with B(OMe)₃ andsubsequent hydrolysis] according to the general procedure B. Obtained asa yellow solid (0.96 g).

MS (EI) 392 (M⁺).

Example B15 (2′,4′-Difluoro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 2,4-difluorobenzene boronic acid according to thegeneral procedure B. Obtained as a yellow solid (3.26 g).

MS (ISN) 349 [(M−H)⁻].

Example B16 (2′-Fluoro-6′-methoxy-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 2-fluoro-6-methoxybenzene boronic acid according to thegeneral procedure B. Obtained as a yellow solid (0.95 g).

MS (ISN) 361 [(M−H)⁻]; mp 65–68° C.

Example B17 (2′,5′-Difluoro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and 2,5-difluorobenzene boronic acid according to thegeneral procedure B. Obtained as a yellow solid (2.85 g).

MS (ISN) 349 [(M−H)⁻]; mp 104° C.

Example B18 (4-Benzofuran-2-yl-2-nitro-phenyl)-carbamic acid tert.-butylester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) and benzo[b]furan-2-boronic acid according to the generalprocedure B. Obtained as an orange solid (711 mg).

MS (EI) 354 (M⁺); mp 175–177° C.

Example B19 (2′,3′-Difluoro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester.

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) (3.64 g, 10 mmol) and 2,3-difluorobenzene boronic acid(2.35 g, 14.9 mmol) according to the general procedure B. Obtained as ayellow solid (3.22 g).

MS (ISN) 349 [(M−H)⁻]; mp 93° C.

General Procedure C (Synthetic Scheme C)

Preparation of (4-aryl-2-nitro-phenyl)-carbamic acid tert.-butyl estersby Suzuki-coupling of (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butylesters with bis(pinacolato)diboron and subsequent reaction with arylhalides.

A mixture of the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(2.0 mmol), bis(pinacolato)diboron (2.2 mmol), KOAc (6.0 mmol) andPdCl₂(PPh₃)₂ (3 mol %) in 1,4-dioxane (25 mL) was stirred at 100° C.until tlc indicated complete conversion of the iodide [cf. Tetr. Lett.1997, 38, 3841–3844]. After addition of the aryl halide (4.0 mmol),PdCl₂(PPh₃)₂ (3 mol %) and 2M Na₂CO₃-sol. (7.5 mL) the mixture wasstirred at 100° C. until tlc indicated complete conversion of theintermediate boronic ester. The mixture was transferred into aseparating funnel, H₂O (30 mL) was added and the product was extractedwith ether or EtOAc (3×50 mL). The combined organic layers were washedwith brine (100 mL) and dried over Na₂SO₄. Removal of the solvent left abrown residue, which was purified by silica gel column chromatographywith cyclohexane/ether or cyclohexane/EtOAc to give the title compound.

Example C1 (2′-Methoxy-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and 2-iodoanisole according to thegeneral procedure C. Obtained as a yellow solid (735 mg).

MS (EI) 344 (M⁺)

Example C2 (4′-Chloro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and l-chloro-4-iodobenzeneaccording to the general procedure C. Obtained as a yellow solid (779mg).

MS (ISN) 347 [(M−H)⁻]; mp 150–155° C. (dec.).

Example C3 (2-Nitro-4-thiophen-2-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and 2-iodothiophene according tothe general procedure C. Obtained as a yellow solid (91 mg).

MS (ISN) 319 [(M−H)⁻].

Example C4 (4′-Methyl-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and 4-iodotoluene according to thegeneral procedure C. Obtained as an orange solid (542 mg).

MS (ISP) 346 [(M+NH₄)⁺] and 367 [(M+Na)⁺]; mp 105–108° C.

Example C5 (2-Nitro-4-pyridin-2-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and 2-bromopyridine according tothe general procedure C. Obtained as a yellow solid (407 mg).

MS (ISP) 316 [(M+H)⁺].

Example C6 (3′-Methyl-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and 3-iodotoluene according to thegeneral procedure C. Obtained as a yellow solid (524 mg).

MS (ISP) 346 (M⁺) and 674 [(2M+NH₄)⁺]; mp 83–85° C.

Example C7 (3′,4′-Dichloro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and 3,4-dichloro-iodobenzeneaccording to the general procedure C. Obtained as a yellow solid (540mg).

MS (EI) 382 (M⁺).

Example C8 (2′-Chloro-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and l-chloro-2-iodobenzeneaccording to the general procedure C. Obtained as a yellow oil (886 mg).

MS (ISN) 347 [(M−H)⁻].

Example C9 (2′-Methyl-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and 2-iodotoluene according to thegeneral procedure C. Obtained as a yellow oil (755 mg).

MS (ISN) 327 [(M−H)⁺⁻].

Example C10 (2-Nitro-4-pyridin-3-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and 3-bromopyridine according tothe general procedure C. Obtained as a yellow solid (587 mg).

MS (ISP) 316 [(M+H)⁺]; mp 107–109° C.

Example C11 (2-Nitro-4-pyridin-4-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and 4-bromopyridine according tothe general procedure C. Obtained as a yellow solid (379 mg).

MS (ISP) 316 [(M+H)⁺].

Example C12 (3″-Nitro-[1,1′;4′,1″]terphenyl-4″-yl)-carbamic acidtert.-butyl ester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and 4-bromobiphenyl according tothe general procedure C. Obtained as a yellow solid (1.29 g).

MS (EI) 390 (M⁺).

Example C13 (4′-Cyano-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1), bis(pinacolato)diboron and 4-bromobenzonitrile accordingto the general procedure C. Obtained as a yellow solid (1.38 g).

MS (ISN) 338 [(M−H)⁻].

General Procedure D (Synthetic Scheme C)

Preparation of (4-aroyl-2-nitro-phenyl)-carbamic acid tert.-butyl estersby carbonylative Suzuki-coupling of (4-iodo-2-nitro-phenyl)-carbamicacid tert.-butyl esters with aryl boronic acids

A mixture of the (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(1.0 mmol), aryl boronic acid (1.1 mmol), K₂CO₃ (3.0 mmol) andPdCl₂(PPh₃)₂ (3 mol %) in anisole (6 mL) was stirred at 80° C. under aCO-atmosphere until tlc indicated complete conversion of the iodide [cf.Tetr. Lett. 1993, 34, 7595–7598]. The mixture was transferred into aseparating funnel, H₂O (30 mL) was added and the product was extractedwith EtOAc (2×100 mL). The combined organic layers were washed withbrine (50 mL) and dried over Na₂SO₄. Removal of the solvent left ayellow residue, which was purified by silica gel column chromatographywith or hexane/EtOAc to give the title compound.

Example D1 (4-Benzoyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) (364 mg, 1.0 mmol) and phenylboronic acid (134 mg, 1.1mmol) according to the general procedure D. Obtained as a yellow solid(242 mg).

MS (EI) 342 (M⁺).

Example D2 (2-Nitro-4-tributylstannanyl-phenyl)-carbamic acidtert.-butyl ester

A solution of (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) (3.64 g, 10 mmol), hexabutyldistannane (7.5 mL, 15 mmol)and (Ph₃P)₄Pd (116 mg, 0.1 mmol) in toluene (20 mL) was heated to 60° C.for 5 days [cf. Bull. Chem. Soc. Jpn. 1983, 56, 3855–3856]. The reactionmixture was diluted with toluene (150 mL), washed with aqueous KF-sol.(2×50 mL), brine and dried over MgSO₄. Removal of the solvent in vacuumleft a brown oil, which was purified by silica gel column chromatographywith hexane/ether 49:1 to give the(2-nitro-4-tributylstannanyl-phenyl)-carbamic acid tert.-butyl ester asa yellow liquid (3.8 g, 72%).

MS (EI) 467, 469, 471 [all (M-butyl)⁺].

General Procedure E (Synthetic Scheme C)

Preparation of (4-aryl-2-nitro-phenyl)-carbamic acid tert.-butyl estersor (4-{alkenyl-, cycloalkenyl- orheterocycloalkenyl}-2-nitro-phenyl)-carbamic acid tert.-butyl esters byStille-coupling of (2-nitro-4-tributylstannanyl-phenyl)-carbamic acidtert.-butyl ester with aryl halides or vinyl triflates orStille-coupling of (4-iodo-2-nitrophenyl)-carbamic acid tert.-butylester with trialkylarylstannanes.

A mixture of (2-nitro-4-tributylstannanyl-phenyl)-carbamic acidtert.-butyl ester (Example D2) (525 mg, 1.0 mmol), aryl halide or vinyltriflate (0.95–6.0 mmol), anhydrous LiCl (126 mg, 3.0 mmol) andPd(PPh₃)₄ (5 mol %) in DME (3 mL) was stirred at 100° C. under argonatmosphere until tlc indicated complete consumption of the stannane. Thereaction was cooled to 23° C., stirred with sat. aqueous KF-sol. (5 mL)for 45 min, filtered through celite, washed with ether and the filtratewas dried over MgSO₄. Removal of the solvent in vacuum left a brown oil,which was purified by silica gel column chromatography with hexane/EtOActo give the title compound.

Example E14-(4-tert.-Butoxycarbonylamino-3-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert.-butyl ester

Prepared from (2-nitro-4-tributylstannanyl-phenyl)-carbamic acidtert.-butyl ester (Example D2) (3.18 g, 6.06 mmol) and4-trifluoromethylsulfonyloxy-3,6-dihydro-2H-pyridine-1-carboxylic acidtert.-butyl ester (1.99 g, 6.0 mmol) [prepared from Boc-4-piperidone bytreatment with LDA in THF at −78° C. followed by reaction withN-phenyl-bis(trifluoromethanesulfonimide) according to Wustrow et al.Synthesis 1991, 1993] according to the general procedure E. Obtained asan orange solid (1.304 g, 52%).

MS (ISP) 420 [(M+H)⁺], 442 [(M+Na)⁺] and 458 [(M+K)⁺]; mp 85–87° C.

Example E2 (2-Nitro-4-thiazol-2-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (2-nitro-4-tributylstannanyl-phenyl)-carbamic acidtert.-butyl ester (Example D2) (1.0 g, 1.9 mmol) and 2-bromothiazole(0.56 mL, 6.27 mmol) according to the general procedure E. Obtained as ayellow solid (160 mg). MS (EI) 321 (M⁺).

Example E3 [4-(6-Benzyloxy-pyridin-3-yl)-2-nitro-phenyl]-carbamic acidtert.-butyl ester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) (728 mg, 2.0 mmol) and2-(phenylmethoxy)-5-(trimethylstannyl)-pyridine (766 mg, 2.2 mmol)[CAS-No. [188881-22-3], WO 9709311] according to the general procedureE. Obtained as a yellow solid (876 mg).

MS (ISP) 422 [(M+H)⁺]; mp 119–122° C.

General Procedure F (Synthetic Scheme E):

Preparation of (4-alkynyl-2-nitro-phenyl)-carbamic acid tert.-butylesters by Sonogashira-coupling of (4-iodo-2-nitro-phenyl)-carbamic acidtert.-butyl esters with acetylenic compounds; also Sonogashira-couplingof (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl esters with arylhalides; and Sonogashira-coupling of8-iodo-4-aryl-1,3-dihydro-benzo[b][1,4]diazepin-2-ones with acetyleniccompounds.

A mixture of the halide (3.0–4.5 mmol), acetylenic compound (3.0–4.5mmol), Et₃N (13.5 mmol), PdCl₂(PPh₃)₂ (5 mol %) and PPh₃ (2.5 mol %) inTHF (12 mL) [with very insoluble material DMF (up to 12 mL) could beadded] was stirred for 20 min at 23° C. while being purged with Argon.CuI (1.2 mol %) was added and stirring was continued at 60° C. underArgon atmosphere until tlc indicated complete conversion of the minorcomponent [cf. J. Org. Chem. 1998, 63, 8551]. The mixture wastransferred into a separating funnel, 5% citric acid (50 mL) was addedand the product was extracted with EtOAc (2×100 mL). The combinedorganic layers were washed with sat. NaHCO₃-sol. (50 mL) and brine (50mL), followed by drying over MgSO₄. Removal of the solvent left a yellowresidue, which was purified by silica gel column chromatography withhexane/EtOAc and/or triturated with hexane or aqueous EtOH to give thetitle compound.

Example F1 (2-Nitro-4-trimethylsilanylethynyl-phenyl)-carbamic acidtert.-butyl ester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) (3.64 g, 10 mmol) and trimethylsilylacetylene (4.2 mL, 30mmol) according to the general procedure F. Obtained as a green oil (3.6g).

MS (EI) 334 (M⁺).

Example F2 (4-Ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester

To a solution of (2-nitro-4-trimethylsilanylethynyl-phenyl)-carbamicacid tert.-butyl ester (Example F1) (3.54 g, 10.6 mmol) in MeOH (10 mL)and THF (20 mL) at 0° C. was added 1N NaOH (13 mL) and stirring wascontinued at 23° C. for 30 min. Poured into cold 5% citric acid,extracted with EtOAc (300 mL), washed with sat. NaHCO₃-sol. and brine,dried over MgSO₄. Removal of the solvent in vacuum left a dark brownoil, which was purified by silica gel column chromatography withhexane/EtOAc 19:1. Obtained as a yellow solid (2.4 g).

MS (EI) 262 (M⁺); mp 102° C.

Example F3 (2-Nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) (5.64 g, 15 mmol) and phenylacetylene (2.47 mL, 22.5 mmol)according to the general procedure F. Obtained as a yellow solid (4.96g).

MS (EI) 338 (M⁺); mp 146–148° C.

Example F4 (2-Nitro-4-p-tolylethynyl-phenyl)-carbamic acid tert.-butylester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) (728 mg, 2.0 mmol) and 4-tolylacetylene (349 mg, 3.0 mmol)according to the general procedure F. Obtained as a yellow solid (632mg).

MS (EI) 352 (M⁺); mp 164–165° C.

Example F5 [4-(2-Chloro-phenylethynyl)-2-nitro-phenyl]-carbamic acidtert.-butyl ester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) (1.82 g, 5.0 mmol) and 2-chlorophenylacetylene (1.02 g, 7.5mmol) according to the general procedure F. Obtained as a yellow solid(1.8 g).

MS (ISN) 371 [(M−H)−] and 373 [(M+2-H)−]; mp 152–155° C.

Example F6 [4-(4-Chloro-phenylethynyl)-2-nitro-phenyl]-carbamic acidtert.-butyl ester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) (728 mg, 2.0 mmol) and 4-chlorophenylacetylene (416 mg, 3.0mmol) according to the general procedure F. Obtained as a yellow solid(658 mg).

MS (EI) 372 (M⁺) and 374 [(M+2)⁺]; mp 213–218° C.

Example F7 (2-Nitro-4-thiazol-2-ylethynyl-phenyl)-carbamic acidtert.-butyl ester

Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example F2) (262 mg, 1.00 mmol) and 2-bromothiazole (0.14 mL, 1.50mmol) according to the general procedure F. Obtained as a yellow solid(215 mg). MS (ISN) 344 [(M−H)⁻]; mp 137° C.

Example F8 (2-Nitro-4-pyridin-2-ylethynyl-phenyl)-carbamic acidtert.-butyl ester

Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example F2) (262 mg, 1.0 mmol) and 2-bromopyridine (0.15 mL, 1.6 mmol)according to the general procedure F. Obtained as a yellow solid (293mg).

MS (ISP) 340 [(M+H)⁺]; mp 142–144° C.

Example F9 [4-(4-Fluoro-phenylethynyl)-2-nitro-phenyl]-carbamic acidtert.-butyl ester

Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example F2) (525 mg, 2.0 mmol) and 1-fluoro-4-iodobenzene (0.35 mL, 3mmol) according to the general procedure F. Obtained as a yellow solid(793 mg).

MS (ISN) 355 [(M−H)⁻]; mp 157–158° C.

Example F10 [4-(2-Fluoro-phenylethynyl)-2-nitro-phenyl]-carbamic acidtert.-butyl ester

Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example F2) (525 mg, 2.0 mmol) and 2-fluoro-1-iodobenzene (0.35 mL, 3mmol) according to the general procedure F. Obtained as a yellow solid(759 mg).

MS (ISN) 355 [(M−H)⁻]; mp 140–142° C.

Example F11 [4-(2,4-Difluoro-phenylethynyl)-2-nitro-phenyl]-carbamicacid tert.-butyl ester

Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example F2) (525 mg, 2.0 mmol) and 2,4-difluoro-1-iodobenzene (0.36 mL,3 mmol) according to the general procedure F. Obtained as a yellow solid(807 mg).

MS (ISN) 373 [(M−H)⁻]; mp 134–136° C.

Example F12[2-Nitro-4-(4-trifluoromethoxy-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester

Prepared from (4-ethynyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example F2) (701 mg, 2.67 mmol) and 1-iodo-4-(trifluoromethoxy)benzene(1.0 g, 3.47 mmol) according to the general procedure F. Obtained as ayellow solid (1.10 g).

MS (ISN) 421 [(M−H)⁻]; mp 129–131° C.

General Procedure G (Synthetic Scheme E)

Preparation of the (2-amino-phenyl)-carbamic acid tert.-butyl esters byreduction of (2-nitro-phenyl)-carbamic acid tert.-butyl esters; Alsopreparation of 4-aryl-1,3-dihydro-benzo[b][1,4]diazepin-2-ones byreduction and concomitant cyclization of3-aryl-N-(2-nitro-phenyl)-3-oxo-propionamides.

Method a: Catalytic Hydrogenation

A mixture of the nitro compound (1.0 mmol) in MeOH or EtOH and THF (1:1to 1:9 ca. 20 mL) and 10% Palladium on carbon (20 mg) or Raney-Ni (20mg) was stirred vigorously at 23° C. under hydrogen atmosphere until tlcindicated complete conversion. The catalyst was filtered off, washedthoroughly with MeOH or EtOH and THF (1:1), the solvent was removed invacuum to give the title compound, which was generally pure enough forfurther transformations.

Method b: Reduction with SnCl₂.*2H₂O

A mixture of the nitro compound (1.0 mmol) and SnCl₂.2H₂O (5.0 mmol) inEtOH (30 mL) was stirred at 70–80° C. under Argon atmosphere until tlcindicated complete conversion [cf. Tetr. Lett. 1984, 25, 839]. Thereaction mixture was brought to pH 8 by addition of sat. NaHCO₃-sol. andextracted with EtOAc (2×100 mL). The combined organic layer were washedwith brine and dried over Na₂SO₄. Removal of the solvent left a yellowsolid, which—if necessary—can be purified by silica gel columnchromatography.

Method c: Reduction with Zn and NH₄Cl

To a mixture of the nitro compound (1.0 mmol) in EtOH/THF/sat.NH₄Cl-sol. (1:1:1, 30 mL) was added Zinc dust (3.0 mmol) and the mixturewas stirred at 70° C. under Argon atmosphere until tlc indicatedcomplete conversion. Aqueous workup as described in method b.

Method d: Reduction with Fe and HOAc

To a mixture of the nitro compound (1.0 mmol) in THF/H₂O (4:1, 10–50 mL)was added Fe powder (6.0 mmol), followed by HOAc (10–12 drops) and themixture was stirred at 70° C. under Argon atmosphere until tlc indicatedcomplete conversion. Aqueous workup as described in method b.

Example G1 (2-Amino-4-iodo-phenyl)-carbamic acid tert.-butyl ester

Prepared from (4-iodo-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example A1) (2.18 g, 6.0 mmol) by reduction with SnCl₂.2H₂O (6.77 g, 30mmol) according to the general procedure G (method b). Obtained as abrown-yellow solid (2.0 g).

MS (EI) 334 (M⁺); mp 127–130° C.

Example G2 (2-Amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester

Prepared from (2-nitro-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example F3) (403 mg, 1.19 mmol) by reduction with SnCl₂.2H₂O(1.34 g, 5.96 mmol) according to the general procedure G (method b).Obtained as an orange solid (237 mg).

MS (ISP) 309 [(M+H)⁺]; mp 177–178° C.

Example G3 (2-Amino-4-p-tolylethynyl-phenyl)-carbamic acid tert.-butylester

Prepared from (2-nitro-4-p-tolylethynyl-phenyl)-carbamic acidtert.-butyl ester (Example F4) (640 mg, 1.82 mmol) by reduction withSnCl₂.2H₂O (2.0 g, 9.1 mmol) according to the general procedure G(method b). Obtained as a beige solid (569 mg).

MS (ISP) 323 [(M+H)⁺]; mp 175° C.

Example G4 [2-Amino-4-(2-chloro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester

Prepared from (4-(2-chloro-phenylethynyl)-2-nitro-phenyl)-carbamic acidtert.-butyl ester (Example F5) (1.61 g, 4.3 mmol) by reduction withSnCl₂.2H₂O (5.3 g, 23.5 mmol) according to the general procedure G(method b). Obtained as a light brown solid (1.1 g).

MS (EI) 342 (M⁺) and 344 [(M+2)⁺]; mp 120–122° C.

Example G5 (3-Amino-4′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4′-methoxy-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B1) by catalytic hydrogenation with Raney-Niaccording to the general procedure G (method a). Obtained as a whitesolid (77 mg).

MS (ISP) 315 [(M+H)⁺] and 337 [(M+Na)⁺].

Example G6 (2-Amino-4-thiophen-3-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (2-nitro-4-thiophen-3-yl-phenyl)-carbamic acid tert.-butylester (Example B2) by catalytic hydrogenation with Raney-Ni according tothe general procedure G (method a). Obtained as a white solid (278 mg).

MS (ISP) 291 [(M+H)⁺].

Example G7 (2-Amino-4-furan-2-yl-phenyl)-carbamic acid tert.-butyl ester

Prepared from (4-furan-2-yl-2-nitrophenyl)-carbamic acid tert.-butylester (Example B3) by catalytic hydrogenation with Raney-Ni according tothe general procedure G (method a). Obtained as a grey powder (212 mg).

MS (EI) 274 (M⁺).

Example G8 (3-Amino-4′-ethyl-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4′-ethyl-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester (Example B4) by catalytic hydrogenation with Raney-Ni according tothe general procedure G (method a). Obtained as a white solid (311 mg).

MS (ISP) 313 [(M+H)⁺] and 335 [(M+Na)⁺].

Example G9 (3-Amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester

Prepared from (3-nitro-biphenyl-4-yl)-carbamic acid tert.-butyl ester(Example B5) (100 mg, 0.32 mmol) by catalytic hydrogenation with Pd/Caccording to the general procedure G (method a). Obtained as a whitesolid (85 mg).

MS (ISP) 285 [(M+H)⁺]; mp 137° C.

Example G10 (3-Amino-2′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (2′-methoxy-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example C1) by catalytic hydrogenation with Raney-Niaccording to the general procedure G (method a). Obtained as a whitesolid (169 mg).

MS (ISP) 315 [(M+H)⁺].

Example G11 (2-Amino-4-furan-3-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (4-furan-3-yl-2-nitrophenyl)-carbamic acid tert.-butylester (Example B6) by catalytic hydrogenation with Raney-Ni according tothe general procedure G (method a). Obtained as a light brown solid.(744 mg).

MS (ISP) 275 [(M+H)⁺] and 297 [(M+Na)⁺]; mp 158–161° C. (dec.).

Example G12 (3-Amino-4′-chloro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4′-chloro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example C2) by reduction with Zn/NH₄Cl according tothe general procedure G (method c). Obtained as a green solid (162 mg).

MS (EI) 318 (M⁺).

Example G13 [2-Amino-4-(4-chloro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester

Prepared from (4-(4-chloro-phenylethynyl)-2-nitro-phenyl)-carbamic acidtert.-butyl ester (Example F6) (606 mg, 1.63 mmol) by reduction withSnCl₂.2H₂O (1.83 g, 8.1 mmol) according to the general procedure G(method b). Obtained as a beige solid (406 mg).

MS (ISP) 343 [(M+H)⁺]and 345 [(M+2+H)⁺]; mp 170–173° C.

Example G14 (2-Amino-4-naphthalen-1-yl-phenyl)-carbamic acid tert.-butylester.

Prepared from (4-naphthalen-1-yl-2-nitro-phenyl)-carbamic acidtert.-butyl ester (Example B7) by catalytic hydrogenation with Raney-Niaccording to the general procedure G (method a). Obtained as a whitesolid (226 mg).

MS (EI) 334 (M⁺).

Example G15 (2-Amino-4-thiazol-2-ylethynyl-phenyl)-carbamic acidtert.-butyl ester

Prepared from (2-nitro-4-thiazol-2-ylethynyl-phenyl)-carbamic acidtert.-butyl ester (Example F7) (205 mg, 0.59 mmol) by reduction withSnCl₂.2H₂O (668 mg, 2.95 mmol) according to the general procedure G(method b). Obtained as a yellow solid (108 mg).

MS (ISP) 316 [(M+H)⁺]; mp 182° C.

Example G16 (3-Amino-4′-methyl-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4′-methyl-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example C4) by catalytic hydrogenation with Pd/Caccording to the general procedure G (method a). Obtained as a whitesolid (125 mg).

MS (ISP) 299 [(M+H)⁺], 321 [(M+Na)⁺] and 337 [(M+K)⁺].

Example G17 (2-Amino-4-pyridin-2-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (2-nitro-4-pyridin-2-yl-phenyl)-carbamic acid tert.-butylester (Example C5) by catalytic hydrogenation with Raney-Ni according tothe general procedure G (method a). Obtained as a light brown solid (339mg).

MS (ISP) 286 [(M+H)⁺] and 308 [(M+Na)⁺].

Example G18 (2-Amino-4-thiophen-2-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (2-nitro-4-thiophen-2-yl-phenyl)-carbamic acid tert.-butylester (Example C3) by catalytic hydrogenation with Pd/C according to thegeneral procedure G (method a). Obtained as a beige powder (151 mg).

MS (ISP) 291 [(M+H)⁺].

Example G19 (2-Amino-4-pyridin-2-ylethynyl-phenyl)-carbamic acidtert.-butyl ester

Prepared from (2-nitro-4-pyridin-2-ylethynyl-phenyl)-carbamic acidtert.-butyl ester (Example F8) (262 mg, 0.772 mmol) by reduction withSnCl₂.2H₂O (871 mg, 3.86 mmol) according to the general procedure G(method b). Obtained as a light brown solid (130 mg).

MS (EI) 309 (M⁺); mp 178° C.

Example G20 (3-Amino-3′-methyl-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (3′-methyl-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example C6) by catalytic hydrogenation with Raney-Niaccording to the general procedure G (method a). Obtained as a whitepowder (212 mg).

MS (EI) 298 (M⁺).

Example G21 (3-Amino-3′,4′-dichloro-biphenyl-4-yl)-carbamic acidtert.-butyl ester

Prepared from (3′,4′-dichloro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example C7) by catalytic hydrogenation with Raney-Niaccording to the general procedure G (method a). Obtained as a whitesolid (485 mg).

MS (ISP) 353 (M⁺); mp 168–171° C.

Example G22 (3-Amino-2′-chloro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (2′-chloro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example C8) by catalytic hydrogenation with Raney-Niaccording to the general procedure G (method a). Obtained as a whitesolid (180 mg).

MS (ISP) 319 [(M+H)⁺], 341 [(M+Na)⁺] and 357 [(M+K)⁺].

Example G23 (3-Amino-2′-methyl-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (2′-methyl-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example C9) by catalytic hydrogenation with Raney-Niaccording to the general procedure G (method a). Obtained as a whitepowder (281 mg).

MS (ISP) 299 [(M+H)⁺], 321 [(M+Na)⁺] and 337 [(M+K)⁺].

Example G24 (2-Amino-4-benzoyl-phenyl)-carbamic acid tert.-butyl ester

Prepared from (4-benzoyl-2-nitro-phenyl)-carbamic acid tert.-butyl ester(Example D1) (280 mg, 0.82 mmol) by catalytic hydrogenation withRaney-Ni according to the general procedure G (method a). Obtained as ayellow foam (269 mg).

MS (ISP) 313 [(M+H)⁺].

Example G25 (3-Amino-3′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (3′-methoxy-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B8) by catalytic hydrogenation with Raney-Niaccording to the general procedure G (method a). Obtained as a whitesolid (165 mg).

MS (ISP) 315 [(M+H)⁺].

Example G26 (2-Amino-4-pyridin-3-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (2-nitro-4-pyridin-3-yl-phenyl)-carbamic acid tert.-butylester (Example C10) by catalytic hydrogenation with Raney-Ni accordingto the general procedure G (method a). Obtained as a grey powder (200mg).

MS (ISP) 286 [(M+H)⁺].

Example G27 (3-Amino-4′-trifluoromethoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester

Prepared from (3-nitro-4′-trifluoromethoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B9) by catalytic hydrogenation with Raney-Niaccording to the general procedure G (method a). Obtained as a whitesolid (371 mg).

MS (ISP) 369 [(M+H)⁺] and 391 [(M+Na)⁺].

Example G28 (2-Amino-4-pyridin-4-yl-phenyl)-carbamic acid tert.-butylester.

Prepared from (2-nitro-4-pyridin-4-yl-phenyl)-carbamic acid tert.-butylester (Example C11) by catalytic hydrogenation with Raney-Ni accordingto the general procedure G (method a). Obtained as a light grey powder(305 mg).

MS (ISP) 286 [(M+H)⁺].

Example G294-(3-Amino-4-tert.-butoxycarbonylamino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert.-butyl ester

Prepared from4-(4-tert.-butoxycarbonylamino-3-nitro-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert.-butyl ester (Example E1) (256 mg, 0.61 mmol) by reductionwith Zn/NH₄Cl according to the general procedure G (method c). Obtainedas an orange foam (75 mg).

MS (EI) 389 (M⁺).

Example G30 [2-Amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamic acidtert.-butyl ester

Prepared from [4-(6-benzyloxy-pyridin-3-yl)-2-nitro-phenyl]-carbamicacid tert.-butyl ester (Example E3) (768 mg, 1.82 mmol) by reductionwith Zn/NH₄Cl according to the general procedure G (method c). Obtainedas a light brown solid (678 mg).

MS (ISP) 392 [(M+H)⁺]; mp 176–177° C.

Example G31 [2-Amino-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamicacid tert.-butyl ester (Example G30) (160 mg, 0.409 mmol) by catalytichydrogenation with Pd/C according to the general procedure G (method a).Obtained as an off-white solid (136 mg).

MS (ISP) 302 [(M+H)⁺]; mp 120–124° C. (dec.).

Example G32 (3″-Amino-[1,1′;4′,1″]terphenyl-4″-yl)-carbamic acidtert.-butyl ester

Prepared from (3″-nitro-[1,1′;4′,1″]terphenyl-4″-yl)-carbamic acidtert.-butyl ester (Example C12) (160 mg, 0.409 mmol) by catalytichydrogenation with Pd/C according to the general procedure G (method a).Obtained as a beige solid (175 mg).

MS (ISP) 361 [(M+H)⁺]; mp 206–207° C.

Example G33 [2-Amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester

Prepared from [4-(4-fluoro-phenylethynyl)-2-nitro-phenyl]-carbamic acidtert.-butyl ester (Example F9) (10.0 g, 28.1 mmol) by reduction withSnCl₂.2H₂O (31.7 g, 140.5 mmol) according to the general procedure G(method b). Obtained as a yellow solid (7.08 g).

MS (ISP) 327 [(M+H)⁺]; mp 180° C.

Example G34 [2-Amino-4-(2-fluoro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester

Prepared from [4-(2-fluoro-phenylethynyl)-2-nitro-phenyl]-carbamic acidtert.-butyl ester (Example F10) (713 mg, 2 mmol) by reduction withSnCl₂.2H₂O (2.26 g, 10 mmol) according to the general procedure G(method b). Obtained as an orange solid (757 mg).

MS (ISP) 327 [(M+H)⁺]; mp 137–139° C.

Example G35 [2-Amino-4-(2,4-difluoro-phenylethynyl)-phenyl]-carbamicacid tert.-butyl ester

Prepared from [4-(2,4-difluoro-phenylethynyl)-2-nitro-phenyl]-carbamicacid tert.-butyl ester (Example F11) (750 mg, 2 mmol) by reduction withSnCl₂.2H₂O (2.26 g, 10 mmol) according to the general procedure G(method b). Obtained as a brown solid (688 mg).

MS (ISP) 345 [(M+H)⁺]; mp 113–116° C.

Example G36[2-Amino-4-(4-trifluoromethoxy-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester

Prepared from[2-nitro-4-(4-trifluoromethoxy-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example F12) (1.09 g, 2.58 mmol) by reduction withSnCl₂₂H₂O (2.91 g, 12.9 mmol) according to the general procedure G(method b). Obtained as a light brown solid (690 mg).

MS (ISP) 393 [(M+H)⁺]; mp 167–169° C.

Example G37 (3-Amino-2′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (2′-fluoro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B10) by catalytic hydrogenation with Pd/Caccording to the general procedure G (method a). Obtained as a yellowsolid (1.31 g).

MS (ISP) 303 [(M+H)⁺]; mp 100–103° C.

Example G38 (3-Amino-3′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (3′-fluoro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B1) by catalytic hydrogenation with Pd/Caccording to the general procedure G (method a). Obtained as a brownsolid (3.40 g).

MS (ISP) 303 [(M+H)⁺]; mp 125–128° C.

Example G39 (3-Amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4′-fluoro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B12) by catalytic hydrogenation withRaney-Nickel according to the general procedure G (method a). Obtainedas a light yellow solid (3.40 g). MS (ISP) 303 [(M+H)⁺].

Example G40 (3-Amino-4′-cyano-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4′-cyano-3-nitro-biphenyl-4-yl)-carbamic acid tert.-butylester (Example C13) by reduction with SnCl₂.2H₂O according to thegeneral procedure G (method b). Obtained as a yellow solid (360 mg).

MS (ISP) 310 [(M+H)⁺]; mp 195° C. (dec.).

Example G41 (3-Amino-3′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (4′-fluoro-2′-methyl-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B13) by catalytic hydrogenation with Pd/Caccording to the general procedure G (method a). Obtained as a lightyellow solid (1.51 g).

MS (ISP) 317 [(M+H)⁺]; mp 143° C.

Example G42 (3-Amino-4′-fluoro-2′-methoxymethoxy-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from(4′-fluoro-2′-methoxymethoxy-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B14) by catalytic hydrogenation with Pd/Caccording to the general procedure G (method a). Obtained as a lightpurple foam (577 mg).

MS (ISP) 363 [(M+H)⁺].

Example G43 (3-Amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester

Prepared from (2′,4′-difluoro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B15) by catalytic hydrogenation with Pd/Caccording to the general procedure G (method a). Obtained as a lightyellow solid (1.77 g).

MS (ISP) 321 [(M+H)⁺]; mp 120° C. (dec.).

Example G44 (3-Amino-2′-fluoro-6′-methoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester

Prepared from (2′-fluoro-6′-methoxy-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B16) by catalytic hydrogenation with Pd/Caccording to the general procedure G (method a). Obtained as a lightpurple foam (577 mg).

MS (ISP) 333 [(M+H)⁺]; mp 165–167° C.

Example G45 (3-Amino-2′,5′-difluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester

Prepared from (2′,5′-difluoro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B17) by catalytic hydrogenation with Pd/Caccording to the general procedure G (method a). Obtained as a lightyellow gum (2.18 g).

MS (ISN) 319 [(M−H)⁻].

Example G46 (2-Amino-4-benzofuran-2-yl-phenyl)-carbamic acid tert.-butylester

Prepared from (4-benzofuran-2-yl-2-nitro-phenyl)-carbamic acidtert.-butyl ester (Example B18) by reduction with SnCl₂.2H₂O accordingto the general procedure G (method b). Obtained as an orange solid (579mg).

MS (ISN) 323 [(M−H)⁻]; mp 165° C.

Example G47 (2-Amino-4-isopropyl-phenyl)-carbamic acid tert.-butyl ester

Prepared from (4-isopropyl-2-nitro-phenyl)-carbamic acid tert.-butylester (Example A2) by catalytic hydrogenation with Pd/C according to thegeneral procedure G (method a). Obtained as a white solid (12.59 g).

MS (ISP) 251 [(M+H)⁺]; mp 100–101° C.

Example G48 (2-Amino-4-cyclopropyl-phenyl)-carbamic acid tert.-butylester

Prepared from (4-cyclopropyl-2-nitro-phenyl)-carbamic acid tert.-butylester (Example A3) by reduction with SnCl₂.2H₂O according to the generalprocedure G (method b). Obtained as a dark solid (1.96 g).

MS (ISP) 249 [(M+H)⁺].

Example G49 (3-Amino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester

Prepared from (2′,3′-difluoro-3-nitro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example B19) (3.14 g, 8.96 mmol) by catalytichydrogenation with Pd/C according to the general procedure G (method a).Obtained as a green solid (2.91 g).

MS (ISP) 321 [(M+H)⁺]; mp 78° C.

General Procedure H (Synthetic Scheme F)

Method a) Preparation of ethyl or tert.-butyl 3-aryl-3-oxo-propionates

The ethyl or tert.-butyl 3-aryl-3-oxo-propionates were prepared from thearyl acid chlorides and ethyl or tert.-butyl malonate potassium salt[CAS-no. 6148-64-7 and 75486-33-8] with Et₃N and MgCl₂ in CH₃CN at 0° C.to 23° C. according to Synthesis 1993, 290. If the free aryl carboxylicacid was employed in this reaction, it was activated by treatment withethyl chloroformate and Et₃N in THF/CH₃CN at 0° C. prior to reactionwith the malonate salt.

Method b) Preparation of tert.-butyl 3-aryl-3-oxo-propionates

The tert.-butyl 3-aryl-3-oxo-propionates were alternatively preparedfrom the methyl or ethyl aryl esters by treatment with lithiumtert.-butyl acetate [prepared by treatment of tert.-butyl acetate withlithium diisopropylamide in THF at −78° C.] in the presence of lithiumtert.-butoxide according to Synthesis 1985, 45. If the product containedresidual starting material after workup, thus could be removed byselective saponification with LiOH in THF/MeOH/H₂O at 23° C.

Method c) Preparation of 3-aryl-3-oxo-propionic acids

The 3-aryl-3-oxo-propionic acids were prepared from the aryl acidchlorides and bis(trimethylsilyl)malonate with Et₃N and LiBr in CH₃CN at0° C. according to Synth. Commun. 1985, 15, 1039 (method c1) or withn-BuLi in ether at −60° C. to 0° C. according to Synthesis 1979, 787(method c2).

Example H1 3-Oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionic acid ethylester

Prepared from 3-[1,2,4]triazol-4-yl-benzoic acid [prepared by reactionof 3-aminobenzoic acid with hydrazine hydrate and triethyl orthoformatein acetic acid at 120° C.] by activation with ethyl chloroformate/Et₃Nand reaction with ethyl malonate potassium salt with Et₃N and MgCl₂ inCH₃CN according to general procedure H (method a). Obtained as a whitesolid (5.74 g).

MS (EI) 259 (M⁺).

Example H2 3-Oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethylester

Prepared from 3-[1,2,3]triazol-1-yl-benzoic acid [prepared by refluxingof methyl 3-azidobenzoate [CAS-No. 93066-93-4] intrimethylsilylacetylene, followed by saponification with aqueous NaOH inrefluxing EtOH] by activation with ethyl chloroformate/Et₃N and reactionwith ethyl malonate potassium salt with Et₃N and MgCl₂ in CH₃CNaccording to general procedure H (method a). Obtained as a light yellowsolid (2.22 g).

MS (EI) 259 (M⁺); mp 72–74° C.

Example H3 3-(3-Cyano-phenyl)-3-oxo-propionic acid tert-butyl ester

Prepared from methyl 3-cyanobenzoate [CAS-No. 13531-48-1] by treatmentwith lithium tert.-butyl acetate according to general procedure H(method b). Obtained as a light brown oily semisolid. MS (EI) 245 (M⁺).

Example H4 3-(3-Imidazol-1-yl-phenyl)-3-oxo-propionic acid tert.-butylester

Prepared from methyl 3-(1H-imidazol-1-yl)benzoate [prepared from3-(1H-imidazol-1-yl)benzoic acid (J. Med. Chem. 1987, 30, 1342; CAS-No.[108035-47-8] by refluxing in conc. H₂SO₄/MeOH] by treatment withlithium tert.-butyl acetate according to general procedure H (method b).Obtained as an orange-brown oil.

MS (ISP) 287 [(M+H)⁺].

Example H5 3-(2-Imidazol-1-yl-pyridin-4-yl)-3-oxo-propionic acidtert.-butyl ester

Prepared from 2-imidazol-1-yl-isonicotinoyl chloride hydrochloride[prepared by reaction of tert.-butyl 2-chloroisonicotinoate withimidazole and NaH in DMF at 80° C., treatment with formic acid at 50° C.and reaction with thionylchloride in toluene at 100° C.] and tert.-butylmalonate potassium salt with Et₃N and MgCl₂ in CH₃CN according togeneral procedure H (method a). Obtained as a brown solid (10.8 g).

MS (EI) 287 (M⁺); mp 80° C. (dec.).

Example H6 3-Oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acidtert.-butyl ester

Prepared from methyl 3-[1,2,4]triazol-1-yl-benzoate [CAS-No.167626-27-9] by treatment with lithium tert.-butyl acetate according togeneral procedure H (method b). Obtained as an orange liquid (2.41 g).

MS (EI) 287 (M⁺).

Example H7 3-[3-(4-Methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acidtert.-butyl ester.

Prepared from methyl 3-(4-methyl-imidazol-1-yl)-benzoate [prepared thecorresponding acid from 3-isothiocyanatobenzoic acid and2-aminopropionaldehyde dimethyl acetal according to J. Med. Chem. 1987,30, 1342, followed by refluxing in conc. H₂SO₄/MeOH] by treatment withlithium tert.-butyl acetate according to general procedure H (method b).Obtained as a yellow-brown oil (10.69 g).

MS (EI) 300 (M⁺).

Example H8 3-[3-(2-Methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acidtert.-butyl ester

Prepared from ethyl 3-(2-methyl-imidazol-1-yl)-benzoate [prepared byreaction of ethyl 3-aminobenzoate with ethyl acetimidate hydrochloridein EtOH at 0° C., direct treatment with aminoacetaldehyde diethyl acetalin EtOH at 23° C., follwed by addition of conc. H₂SO₄ and refluxing.] bytreatment with lithium tert.-butyl acetate according to generalprocedure H (method b). Obtained as a brown oil (9.66 g).

MS (ISN) 299 [(M−H)⁻].

Example H9 3-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionicacid tert.-butyl ester

Prepared from ethyl 3-(2,4-dimethyl-imidazol-1-yl)-benzoate [prepared byreaction of ethyl 3-aminobenzoate with ethyl acetimidate hydrochloridein EtOH at 0° C., direct treatment with 2-aminopropionaldehyde dimethylacetal in EtOH at 23° C., follwed by addition of conc. H₂SO₄ andrefluxing.] by treatment with lithium tert.-butyl acetate according togeneral procedure H (method b). Obtained as a yellow-brown oil (6.00 g).

MS (ISN) 313 [(M−H)⁻].

Example H10 3-(2-Cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butylester

Prepared from 2-cyano-isonicotinic acid ethyl ester [CAS-No. 58481-14-4]by treatment with lithium tert.-butyl acetate according to generalprocedure H (method b). Obtained as a light brown solid (7.70 g).

MS (ISN) 245 [(M−H)⁻].

Example H11 3-Oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionic acidtert.-butyl ester

Prepared from methyl 3-[1,2,4]triazol-4-yl-benzoate [prepared byreaction of 3-aminobenzoic acid with hydrazine hydrate and triethylorthoformate in acetic acid at 120° C., followed by esterification withconc. H₂SO₄ in refluxing MeOH] by treatment with lithium tert.-butylacetate according to general procedure H (method b). Obtained as a lightyellow gum (870 mg).

MS (ISN) 286 [(M−H)⁻].

Example H123-[3-(2-Methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionicacid tert.-butyl ester

Prepared from ethyl 3-(2-methoxymethylsulfanyl-imidazol-1-yl)-benzoate[prepared by esterification of3-(2-methoxymethylsulfanyl-imidazol-1-yl)-benzoic acid [CAS-No.108035-46-7] with conc. H₂SO₄ in EtOH, followed by treatment withchloromethylmethyl ether and NaH in THF/DMF] by treatment with lithiumtert.-butyl acetate according to general procedure H (method b).Obtained as an orange oil (1.82 g).

MS (EI) 362 (M⁺).

Example H133-[3-(2-Methylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acidtert.-butyl ester

Prepared from ethyl 3-(2-methylsulfanyl-imidazol-1-yl)-benzoate[prepared by esterification of3-(2-methoxymethylsulfanyl-imidazol-1-yl)-benzoic acid [CAS-No.108035-46-7] with conc. H₂SO₄ in EtOH, followed by treatment methyliodide and NaH in THF/DMF] by treatment with lithium tert.-butyl acetateaccording to general procedure H (method b). Obtained as a light brownoil (4.41 g).

MS (ISP) 333 [(M+H)⁺].

Example H14 3-[3-(3-Methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acidtert.-butyl ester

Prepared from ethyl 3-(3-methyl-isoxazol-5-yl)-benzoate [prepared byreaction of ethyl 3-ethynylbenzoate [CAS-No. 178742-95-5] with a mixtureof NCS, acetaldoxime, Et₃N and cat. amount of pyridine in CHCl₃ at 50°C. according to Tetrahedron 1984, 40, 2985–2988] by treatment withlithium tert.-butyl acetate according to general procedure H (method b).Obtained as a yellow solid (2.54 g).

MS (ISP) 302 [(M+H)⁺]; mp 50–56° C.

Example H15 3-Oxo-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl ester

Prepared from 3-tetrazol-1-yl-benzoic acid [CAS-No. 204196-80-5] byactivation with ethyl chloroformate/Et₃N and reaction with ethylmalonate potassium salt with Et₃N and MgCl₂ in CH₃CN according togeneral procedure H (method a). Obtained as a light yellow solid (211mg).

MS (EI) 260 (M⁺).

Example H16 3-(3-Chloro-thiophen-2-yl)-3-oxo-propionic acid ethyl ester

Prepared from 3-chloro-2-thiophenecarbonyl chloride [CAS-No. 86427-02-3]by reaction with ethyl malonate potassium salt with Et₃N and MgCl₂ inCH₃CN according to general procedure H (method a). Obtained as a brownoil (6.84 g).

MS (EI) 232 (M⁺) and 234 [(M+2)⁺].

Example H17 3-(5-Cyano-thiophen-2-yl)-3-oxo-propionic acid tert.-butylester

Prepared from ethyl 5-cyano-2-thiophenecarboxylate [CAS-No. 67808-35-9]by treatment with lithium tert.-butyl acetate according to generalprocedure H (method b). Obtained as a yellow solid (6.66 g).

MS (EI) 251 (M⁺); mp 78° C.

Example H18 3-(5-Cyano-2-fluoro-phenyl)-3-oxo-propionic acid ethyl ester

Prepared from 5-cyano-2-fluoro-benzoyl chloride [prepared from thecorresponding acid [CAS-No. 146328-87-2] by treatment with SOCl₂, cat.DMF in toluene at 80° C.] by reaction with ethyl malonate potassium saltwith Et₃N and MgCl₂ in CH₃CN according to general procedure H (methoda). Obtained as a light yellow solid (3.85 g).

MS (EI) 235 (M⁺); mp 55–60° C.

Example H19 3-(2-Imidazol-1-yl-thiazol-4-yl)-3-oxo-propionic acidtert.-butyl ester

Prepared from ethyl 2-imidazol-1-yl-thiazole-4-carboxylate [CAS-No.256420-32-3] by treatment with lithium tert.-butyl acetate according togeneral procedure H (method b). Obtained as an orange oil (12.0 g).

Example H20 3-[2-(4-Methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionicacid tert.-butyl ester

Prepared from ethyl 2-(4-methyl-imidazol-1-yl)-thiazole-4-carboxylate[prepared from ethyl 2-amino-4-thiazolecarboxylate (CAS-No.[256420-32-3]) by the following synthetic sequence: 1.) NaH,2-isothiocyanato-1,1-dimethoxy-propane, DMF, 23° C.; 2.) aq. H₂SO₄,reflux; 3.) EtOH, conc. H₂SO₄, 23° C.; 4.) 30% H₂O₂, HOAc, 23° C.] bytreatment with lithium tert.-butyl acetate according to generalprocedure H (method b). Obtained as a brown oil (8.73 g).

MS (EI) 307 (M⁺).

Example H21 3-[3-(1-Methyl-1H-imidazol-2-yl)-phenyl]-3-oxo-propionicacid tert.-butyl ester

Prepared from ethyl 3-(1-methyl-1H-imidazol-2-yl)benzoate [CAS-No.168422-44-4] by treatment with lithium tert.-butyl acetate according togeneral procedure H (method b). Obtained as a light yellow liquid (1.26g).

MS (ISP) 301.3 [(M+H)⁺].

General Procedure J (Synthetic Scheme F)

Preparation of 6-aryl-2,2-dimethyl-[1,3]dioxin-4-ones

Method a)

The 6-aryl-2,2-dimethyl-[1,3]dioxin-4-ones were prepared from3-aryl-3-oxo-propionic acids and catalytic amount of conc. H₂SO₄ ortrifluoroacetic acid (TFA) in isopropenyl acetate at 23° C. according toChem. Pharm. Bull. 1983, 31, 1896. The final products were purified bysilica gel column chromatography with hexane/EtOAc.

Method b)

The 6-aryl-2,2-dimethyl-[1,3]dioxin-4-ones were prepared from thetert.-butyl 3-aryl-3-oxo-propionates by treatment with trifluoroaceticanhydride (TFAA) in a mixture of TFA and acetone at 23° C. according toTetrahedron Lett. 1998, 39, 2253. The final products were if necessarypurified by silica gel column chromatography with hexane/EtOAc.

Example J1 2,2-Dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one

The 3-oxo-3-thiophen-2-yl-propionic acid was prepared fromthiophene-2-carbonyl chloride (5.3 mL, 50 mmol) andbis(trimethylsilyl)malonate (25.6 mL, 100 mmol) with n-BuLi (1.6M inhexane, 62.5 mL) in ether at −60° C. to 0° C. according to the generalprocedure H (method c2). The crude material (7.88 g) was transformedinto the title compound by stirring in isopropenyl acetate and TFAaccording to the general procedure J (method a). Obtained as a yellowsolid (4.09 g).

MS (EI) 210 (M⁺); mp 42° C. (dec.).

Example J2 6-(3-Chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one

The 3-(3-chloro-thiophen-2-yl)-3-oxo-propionic acid was prepared from3-chloro-thiophene-2-carbonyl chloride (7.82 g, 43.2 mmol) andbis(trimethylsilyl)malonate (11.6 mL, 45.4 mmol) with Et₃N (12.65 mL,90.7 mmol) and LiBr (3.53 g, 47.5 mmol) in CH₃CN at 0° C. according togeneral procedure H (method c1). The crude material (5.69 g) wastransformed into the title compound by stirring in isopropenyl acetateand conc. H₂SO₄ according to general procedure J (method a). Obtained asan orange solid (2.3 g).

MS (EI) 244 (M⁺) and 246 [(M+2)⁺]; mp 88–89° C. (dec.).

Example J3 6-(3-Cyano-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one

The 3-(3-cyano-thiophen-2-yl)-3-oxo-propionic acid was prepared from3-cyano-thiophene-2-carbonyl chloride (24.33 g, 140.6 mmol) andbis(trimethylsilyl)malonate (38.0 mL, 147.7 mmol) with Et₃N (41 mL,295.4 mmol) and LiBr (13.5 g, 154.7 mmol) in CH₃CN at 0° C. according togeneral procedure H (method c1). The crude material (24.8 g) wastransformed into the title compound by stirring in isopropenyl acetateand conc. H₂SO₄ according to general procedure J (method a). Obtained asan orange solid (5.6 g).

MS (EI) 235 (M⁺); mp 116–120° C. (dec.).

Example J4 3-(2,2-Dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile

The 3-(3-cyano-phenyl)-3-oxo-propionic acid was prepared from3-cyanobenzoyl chloride (828 mg, 5 mmol) and bis(trimethylsilyl)malonate(2.56 mL, 10 mmol) with n-BuLi (1.6M in hexane, 6.25 mL) in ether at−60° C. to 0° C. according to general procedure H (method c2). The crudematerial (1.04 g) was transformed into the title compound by stirring inisopropenyl acetate and TFA according to general procedure J (method a).Obtained as a light yellow solid (0.8 g).

MS (EI) 229 (M⁺); mp 138° C. (dec.).

Example J5 2,2-Dimethyl-6-(3-trifluoromethyl-phenyl)-[1,3]dioxin-4-one

The 3-oxo-3-(3-trifluoromethyl-phenyl)-propionic acid was prepared from3-trifluoromethylbenzoyl chloride (10 mL, 67.6 mmol) andbis(trimethylsilyl)malonate (18.2 mL, 71 mmol) with Et₃N (20 mL, 142mmol) and LiBr (6.46 g, 74.4 mmol) in CH₃CN at 0° C. according togeneral procedure H (method c1). The crude material (7.0 g of theobtained 15.4 g) was transformed into the title compound by stirring inisopropenyl acetate and conc. H₂SO₄ according to general procedure J(method a). Obtained as a light yellow solid (5.3 g).

MS (EI) 272 (M⁺); mp 77–78° C. (dec.).

Example J6 6-(3-Chloro-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one

The 3-(3-chloro-phenyl)-3-oxo-propionic acid was prepared from3-chlorobenzoyl chloride (11 mL, 85.7 mmol) andbis(trimethylsilyl)malonate (23.0 mL, 90.0 mmol) with Et₃N (25 mL, 180mmol) and LiBr (8.19 g, 94.3 mmol) in CH₃CN at 0° C. according togeneral procedure H (method c1). The crude material (17.1 g) wastransformed into the title compound by stirring in isopropenyl acetateand conc. H₂SO₄ according to general procedure J (method a). Obtained asa yellow-brown solid (8.0 g).

MS (EI) 238 (M⁺) and 240 [(M+2)⁺]; mp 87–88° C. (dec.).

Example J7 6-(3-Iodo-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one

The 3-(3-iodo-phenyl)-3-oxo-propionic acid was prepared from3-iodobenzoyl chloride (21.0 g, 78.8 mmol) andbis(trimethylsilyl)malonate (21.0 mL, 82.8 mmol) with Et₃N (23 mL, 165.5mmol) and LiBr (7.54 g, 86.7 mmol) in CH₃CN at 0° C. according togeneral procedure H (method c1). The crude material (21.9 g) wastransformed into the title compound by stirring in isopropenyl acetateand conc. H₂SO₄ according to general procedure J (method a). Obtained asa yellow solid (9.6 g).

MS (EI) 330 (M⁺); mp 79–80° C. (dec.).

Example J8 2,2-Dimethyl-6-(3-trifluoromethoxy-phenyl)-[1,3]dioxin-4-one

The 3-oxo-3-(3-trifluoromethoxy-phenyl)-propionic acid was prepared from3-trifluoromethoxybenzoyl chloride and bis(trimethylsilyl) malonate withEt₃N and LiBr in CH₃CN at 0° C. according to general procedure H (methodc1). The crude material was transformed into the title compound bystirring in isopropenyl acetate and conc. H₂SO₄ according to generalprocedure J (method a). Obtained as an orange solid (2.27 g).

MS (EI) 288 (M⁺); mp 49–54° C. (dec.).

Example J9 2,2-Dimethyl-6-pyridin-4-yl-[1,3]dioxin-4-one

Prepared from 3-oxo-3-pyridin-4-yl-propionic acid [prepared from4-acetylpyridine, magnesium methylcarbonate and CO₂ in DMF at 120° C.according to Journal of Antibiotics 1978, 31, 1245] by treatment withacetone, TFA and TFAA according to general procedure J (method b).Obtained as a white solid (1.3 g).

MS (EI) 205 (M⁺)

Example J10 6-(3-Imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one

The 3-(3-imidazol-1-yl-phenyl)-3-oxo-propionic acid was prepared from3-(1H-imidazol-1-yl)benzoyl chloride hydrochloride [prepared bytreatment of 3-(1H-imidazol-1-yl)benzoic acid (J. Med. Chem. 1987, 30,1342; CAS-No. [108035-47-8] with SOCl₂) and bis(trimethylsilyl)malonatewith Et₃N and LiBr in CH₃CN at 0° C. according to general procedure H(method c1). The crude material was transformed into the title compoundby stirring in isopropenyl acetate and conc. H₂SO₄ according to generalprocedure J (method a). Obtained as an orange semisolid (617 g).

MS (EI) 270 (M⁺).

Example J11 2,2-Dimethyl-6-(3-methoxy-phenyl)-[1,3]dioxin-4-one

The 3-(3-methoxy-phenyl)-3-oxo-propionic acid was prepared from3-methoxybenzoyl chloride (10.3 g, 60.4 mmol) andbis(trimethylsilyl)malonate (16.2 mL, 63.4 mmol) with Et₃N (17.7 mL, 127mmol) and LiBr (5.77 g, 66.4 mmol) in CH₃CN at 0° C. according togeneral procedure H (method c1). The crude material (6.38 g) wastransformed into the title compound by stirring in isopropenyl acetateand conc. H₂SO₄ according to general procedure J (method a). Obtained asa yellow oil (640 mg).

MS (ISP) 235 [(M+H)⁺] and 252 [(M+NH₄)⁺].

Example J12 2,2-Dimethyl-6-(3-nitro-phenyl)-[1,3]dioxin-4-one

The 3-(3-nitro-phenyl)-3-oxo-propionic acid tert.-butyl ester wasprepared from 3-nitrobenzoyl chloride (2.71 g, 14.6 mmol) andtert.-butyl malonate potassium salt (6.0 g, 30.0 mmol) with Et₃N (4.5mL, 32.2 mmol) and MgCl₂ (3.48 g, 36.52 mmol) in CH₃CN according togeneral procedure H (method a). The crude material (3.88 g) wastransformed into the title compound by stirring in TFA/acetone with TFAAaccording to general procedure J (method b). Obtained as a yellow solid(2.76 g).

MS (EI) 249 (M⁺); mp 110–117° C.

Example J132,2-Dimethyl-6-(3-[1,2,4]triazol-1-yl-phenyl)-[1,3]dioxin-4-one

The 3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionic acid tert.-butylester was prepared from 3-[1,2,4]triazol-1-yl-benzoic acid methyl ester[CAS-No. 167626-27-9] by treatment with lithium tert.-butyl acetateaccording to general procedure H (method b). Prepared from (Example H6)by stirring in TFA/acetone with TFAA according to general procedure J(method b). Obtained as a yellow solid (539 mg).

MS (EI) 271 (M⁺).

Example J46-(2-Imidazol-1-yl-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxin-4-one

Prepared from 3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionic acidtert.-butyl ester (Example H5) by stirring in TFA/acetone with TFAAaccording to general procedure J (method b). Obtained as a brown solid(10.8 g).

MS (EI) 271 (M⁺); mp 151° C. (dec.).

Example J152,2-Dimethyl-6-[3-(2-methyl-imidazol-1-yl)-phenyl]-[1,3]dioxin-4-one

Prepared from 3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acidtert.-butyl ester (Example H8) by stirring in TFA/acetone with TFAAaccording to general procedure J (method b). Obtained as a beige solid(2.13 g).

MS (EI) 284 (M⁺); mp 122° C.

Example J164-(2,2-Dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-pyridine-2-carbonitrile

Prepared from 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butylester (Example H10) by stirring in TFA/acetone with TFAA according togeneral procedure J (method b). Obtained as a brown solid (3.30 g).

MS (EI) 230 (M⁺); mp 132° C. (dec.).

General Procedure K (Synthetic Scheme B)

Preparation of {2-[3-aryl-3-oxo-propionylamino]-4-aryl-phenyl}-carbamicacid tert.-butyl ester by reaction of (2-amino-4-aryl-phenyl)-carbamicacid tert.-butyl esters with ethyl or tert.-butyl3-aryl-3-oxo-propionates or 6-aryl-2,2-dimethyl-[1,3]dioxin-4-ones; also3-aryl-N-(2-nitro-4-aryl-phenyl)-3-oxo-propionamides by reaction of2-nitro-4-aryl-phenylamines with 6-aryl-2,2-dimethyl-[1,3]dioxin-4-ones.

A mixture of the (2-amino-4-aryl-phenyl)-carbamic acid tert.-butyl esteror 2-nitro-4-aryl-phenylamine (1.0 mmol) and the ethyl or tert.-butyl3-aryl-3-oxo-propionate or 6-aryl-2,2-dimethyl-[1,3]dioxin-4-one(0.8–1.5 mmol) was refluxed in toluene (4–8 mL) until thin layerchromatography indicated complete consumption of the minor component.The solution was allowed to cool to 23° C., whereupon the productgenerally crystallized (in cases where crystallization failed to appearit was induced by addition of hexane or the entire reaction mixture wasdirectly subjected to chromatography). The solid was filtered off,washed with ether or mixtures of ether/hexane and dried in vacuum togive the {2-[3-aryl-3-oxo-propionylamino]-4-aryl-phenyl}-carbamic acidtert.-butyl esters or3-aryl-N-(2-nitro-4-aryl-phenyl)-3-oxo-propionamides, which was useddirectly in the following step or—if necessary—was purified byrecrystallization or by silica gel column chromatography.

Example K1{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-iodo-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-iodo-phenyl)-carbamic acid tert.-butyl ester(Example G1) (900 mg, 2.7 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionicacid ethyl ester (880 mg, 4.1 mmol) according to the general procedureK. Obtained as a yellow solid (1.2 g).

MS (ISP) 506 [(M+H)⁺] and 528 [(M+Na)⁺]; mp 182–183° C.

Example K2{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example G2) (214 mg, 0.7 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(250 mg, 1.1 mmol) according to the general procedure K. Obtained as alight yellow solid (260 mg).

MS (ISP) 480 [(M+H)⁺], 497 [(M+NH₄)⁺] and 502 [(M+Na)⁺]; mp 168–170° C.(dec.).

Example K3{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4′-methoxy-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-methoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G5) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as a light brown solid(207 mg).

MS (ISP) 486 [(M+H)⁺], 508 [(M+Na)⁺] and 524 [(M+K)⁺]

Example K4{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-thiophen-3-yl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-thiophen-3-yl-phenyl)-carbamic acid tert.-butylester (Example G6) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as a brown solid (104 mg)and used crude in the next step (Example 7).

Example K5{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-furan-2-yl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-furan-2-yl-phenyl)-carbamic acid tert.-butylester (Example G7) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as a beige powder (271mg).

MS (ISP) 446 [(M+H)⁺], 468 [(M+Na)⁺] and 484 [(M+K)⁺]

Example K6{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester(Example G9) (250 mg, 0.88 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(243 mg, 1.06 mmol) according to the general procedure K. Obtained as awhite solid (324 mg).

MS (ISP) 456 [(M+H)⁺]; mp 168° C. (dec.)

Example K7{2-[3-(3-Iodo-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example G2) (1.0 g, 3.24 mmol) and6-(3-iodo-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J7) (1.78 g,3.57 mmol) according to the general procedure K. Obtained as a lightyellow solid (1.9 g).

MS (ISP) 581 [(M+H)⁺] and 603 [(M+Na)⁺]; mp 193–195° C. (dec.)

Example K8{3-[3-(3-Azido-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester(Example G9) (569 mg, 2 mmol) and 3-(3-azido-phenyl)-3-oxo-propionicacid ethyl ester (700 mg, 3 mmol; prepared from 3-azido-benzoyl chloride(Bioorg. Chem 1986, 134) using the procedure described in Synthesis,1993, 290, method A; MS (EI) 233 (M⁺)) according to the generalprocedure K. Obtained as an orange solid (367 mg).

MS (ISP) 472 [(M+H)⁺] and 494 [(M+Na)⁺]

Example K8{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-2′,3′-difluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G49) (160 mg, 0.5 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(115 mg, 0.5 mmol) according to the general procedure K. Obtainedas awhite solid (53 mg).

MS (ISP) 492 [(M+H)⁺]; mp 118° C.

Example K9{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-furan-3-yl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-furan-3-yl-phenyl)-carbamic acid tert.-butylester (Example G11) and 3-(3-cyano-phenyl)-3-oxo-propionic acid ethylester (Pol. J. Chem. 1978, 25) according to the general procedure K.Obtained as an orange solid (460 mg).

MS (ISP) 446 [(M+H)⁺], 463 [(M+NH₄)⁺] and 468 [(M+Na)⁺]

Example K10{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-naphthalen-1-yl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-naphthalen-1-yl-phenyl)-carbamic acidtert.-butyl ester (Example G14) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as an off-white solid (92mg) and used crude in the next step (Example 20).

Example K11{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-thiazol-2-ylethynyl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-thiazol-2-ylethynyl-phenyl)-carbamic acidtert.-butyl ester (Example G11) (89 mg, 0.28 mmol) and3-(3-cyano-phenyl)-3-oxo-propionic acid ethyl ester (Pol. J. Chem. 1978,25) (74 mg, 0.34 mmol) according to the general procedure K. Obtained asa light yellow solid (129 mg).

MS (ISP) 487 [(M+H)⁺]; mp 131° C.

Example K12{2-[3-(3-Chloro-thiophen-2-yl)-3-oxo-propionylamino]-4-pyridin-2-yl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-pyridin-2-yl-phenyl)-carbamic acid tert.-butylester (Example G17) and6-(3-chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J2)according to the general procedure K. Obtained as an amorphous brownsolid (145 mg).

MS (ISP) 472 [(M+H)⁺] and 494 [(M+Na)⁺]

Example K13{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-pyridin-2-yl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-pyridin-2-yl-phenyl)-carbamic acid tert.-butylester (Example G17) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as a light brown solid(90 mg).

MS (ISP) 457 [(M+H)⁺] and 479 [(M+Na)⁺].

Example K14[3-(3-Oxo-3-thiophen-3-yl-propionylamino)-biphenyl-4-yl]-carbamic acidtert.-butyl ester

Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester(Example G9) (144 mg, 0.51 mmol) and 3-oxo-3-thiophen-3-yl-propionicacid ethyl ester (FR 7191887) (151 mg, 0.76 mmol) according to thegeneral procedure K. Obtained as a yellow foam (181 mg).

MS (ISN) 435 [(M+H)⁺].

Example K15{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-3′-methyl-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-3′-methyl-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G20) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as a viscous orange oil(290 mg).

MS (ISP) 470 [(M+H)⁺], 492 [(M+Na)⁺] and 508 [(M+K)⁺].

Example K16{3-[3-(3-Chloro-thiophen-2-yl)-3-oxo-propionylamino]-2′-methyl-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-methyl-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G23) and6-(3-chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J2)according to the general procedure K. Obtained as a viscous brown oil(154 mg).

MS (ISP) 485 [(M+H)⁺], 507 [(M+Na)⁺] and 523 [(M+K)⁺].

Example K17{4-Benzoyl-2-[3-(3-chloro-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-benzoyl-phenyl)-carbamic acid tert.-butyl ester(Example G24) (205 mg, 0.66 mmol) and6-(3-chloro-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J6) (174 mg,0.73 mmol) according to the general procedure K. Obtained as a brownfoam (232 mg).

MS (ISP) 493 [(M+H)⁺].

Example K18{4-Benzoyl-2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-benzoyl-phenyl)-carbamic acid tert.-butyl ester(Example G24) (375 mg, 1.20 mmol) and 3-(3-cyano-phenyl)-3-oxo-propionicacid ethyl ester (Pol. J. Chem. 1978, 25) (313 mg, 1.44 mmol) accordingto the general procedure K. Obtained as a light yellow solid (170 mg).

MS (ISP) 484 [(M+H)⁺], 501 [(M+NH4)⁺] and 506 [(M+Na)⁺]; mp 168° C.(dec.)

Example K19[4-Benzoyl-2-(3-oxo-3-thiophen-2-yl-propionylamino)-phenyl]-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-benzoyl-phenyl)-carbamic acid tert.-butyl ester(Example G24) (259 mg, 0.5 mmol) and2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (Example J1) (135 mg,0.55 mmol) according to the general procedure K. Obtained as a lightyellow solid (60 mg).

MS (ISP) 465 [(M+H)⁺]

Example K20{3-[3-(3-Chloro-thiophen-2-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester(Example G9) (100 mg, 0.35 mmol) and6-(3-chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J2)(95 mg, 0.39 mmol) according to the general procedure K. Obtained as awhite solid (127 mg).

MS (ISP) 471 [(M+H)⁺]; mp 165° C.

Example K21{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-3′-methoxy-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-3′-methoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G25) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as a beige solid (238mg).

MS (ISP) 486 [(M+H)⁺], 508 [(M+Na)⁺] and 524 [(M+K)⁺].

Example K22[5-(6-Oxo-1,6-dihydro-pyridin-3-yl)-2-(3-oxo-3-thiophen-2-yl-propionylamino)-phenyl]-carbamicacid tert.-butyl ester

Prepared from[2-amino-4-(6-oxo-1,6-dihydro-pyridin-3-yl)-phenyl]-carbamic acidtert.-butyl ester (Example G31) (200 mg, 0.664 mmol) and2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (Example J1) (140 mg,0.665 mmol) according to the general procedure K. Obtained as a beigesolid (235 mg).

MS (ISP) 454 [(M+H)⁺]

Example K23{4-(6-Benzyloxy-pyridin-3-yl)-2-[3-oxo-3-(3-trifluoromethyl-phenyl)-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamicacid tert.-butyl ester (Example G30) (203 mg, 0.52 mmol) and2,2-dimethyl-6-(3-trifluoromethyl-phenyl)-[1,3]dioxin-4-one (Example J5)(150 mg, 0.55 mmol) according to the general procedure K. Obtained as anoff-white solid (213 mg).

MS (ISP) 606 [(M+H)⁺]; mp 190° C. (dec.).

Example K24{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4′-trifluoromethoxy-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-trifluoromethoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G27) and 3-(3-cyano-phenyl)-3-oxo-propionicacid ethyl ester (Pol J. Chem. 1978, 25) according to the generalprocedure K. Obtained as a brown semisolid (94 mg).

MS (ISP) 540 [(M+H)⁺], 557 [(M+NH4)⁺] and 562 [(M+Na)⁺].

Example K254-{4-tert.-Butoxycarbonylamino-3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert.-butyl ester

Prepared from4-(3-amino-4-tert.-butoxycarbonylamino-phenyl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert.-butyl ester (Example G29) (544 mg, 1.4 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(336 mg, 1.5 mmol) according to the general procedure K. Obtained as anorange solid (722 mg).

MS (ISP) 561 [(M+H)⁺]; mp 75–79° C. (dec.).

Example K26{4-(6-Benzyloxy-pyridin-3-yl)-2-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamicacid tert.-butyl ester (Example G30) (216 mg, 0.55 mmol) and6-(3-chloro-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J2)(142 mg, 0.58 mmol) according to the general procedure K. Obtained as abeige solid (172 mg).

MS (ISP) 578 [(M+H)⁺]; mp 158–159° C. (dec.).

Example K27{2-[3-(3-Imidazol-1-yl-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example G2) (154 mg, 0.5 mmol) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)(135 mg, 0.5 mmol) according to the general procedure K. Obtained as anorange oil (179 mg).

MS (ISN) 519 [(M−H)⁻].

Example K28{4-Benzofuran-2-yl-2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-benzofuran-2-yl-phenyl)-carbamic acidtert.-butyl ester (Example G46) (324 mg, 1.0 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(252 mg, 1.1 mmol) according to the general procedure K. Obtained as ayellow solid (299 mg).

MS (ISP) 496 [(M+H)⁺]; mp 115° C.

Example K29{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-[1,1′;4′,1″]terphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3″-amino-[1,1′;4′,1″]terphenyl-4″-yl)-carbamic acidtert.-butyl ester (Example G32) (159 mg, 0.44 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(111 mg, 0.49 mmol) according to the general procedure K. Obtained as anoff-white solid (156 mg).

MS (ISN) 530 [(M−H)⁻]; mp 214–216° C.

Example K30[2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-(4-trifluoromethoxy-phenylethynyl)-phenyl]-carbamicacid tert.-butyl ester

Prepared from[2-amino-4-(4-trifluoromethoxy-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G36) (196 mg, 0.5 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(126 mg, 0.55 mmol) according to the general procedure K. Obtained as anoff-white solid (175 mg).

MS (ISP) 564 [(M+H)⁺]; mp 152–154° C.

Example K31{2-[3-(3-Nitro-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example G2) (1.1 g, 4.0 mmol) and2,2-dimethyl-6-(3-nitro-phenyl)-[1,3]dioxin-4-one (Example J12) (1.23 g,4.4 mmol) according to the general procedure K. Obtained as a lightyellow solid (989 mg).

MS (ISN) 498 [(M−H)⁻]; mp 177–179° C.

Example K32{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as a yellow solid (257mg).

MS (ISP) 474 [(M+H)⁺]; mp 177–179° C.

Example K33{4-(4-Fluoro-phenylethynyl)-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G33) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)according to the general procedure K. Obtained as an orange oil (207mg).

MS (ISN) 537 [(M−H)⁻].

Example K34{3-[3-(3-Imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester(Example G9) (142 mg, 0.5 mmol) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)(170 mg, 0.63 mmol) according to the general procedure K. Obtained as alight yellow foam (248 mg).

MS (ISN) 495 [(M−H)⁻].

Example K35{4′-Fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)according to the general procedure K. Obtained as a light yellow solid(489 mg).

MS (ISN) 513 [(M−H)⁻].

Example K36 (3-Amino-4′-methoxy-biphenyl-4-yl)-carbamic acid tert.-butylester

Prepared from (3-amino-4′-methoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G5) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)according to the general procedure K. Obtained as a yellow liquid (195mg).

Example K37{4-(4-Fluoro-phenylethynyl)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G33) and2,2-dimethyl-6-(3-[1,2,4]triazol-1-yl-phenyl)-[1,3]dioxin-4-one (ExampleJ13) according to the general procedure K. Obtained as a yellow solid(230 mg).

mp 131–139° C.

Example K38{4-(2-Fluoro-phenylethynyl)-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(2-fluoro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G34) (245 mg, 0.75 mmol) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)(300 mg, 1.1 mmol) according to the general procedure K. Obtained as ayellow-brown foam (211 mg).

MS (ISN) 537 [(M−H)⁻].

Example K39{4′-Fluoro-3-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) and2,2-dimethyl-6-(3-[1,2,4]triazol-1-yl-phenyl)-[1,3]dioxin-4-one (ExampleJ13) according to the general procedure K. Obtained as an orange foam(233 mg).

Example K40{4′-Cyano-3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-cyano-biphenyl-4-yl)-carbamic acid tert.-butylester (Example G40) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as a light red solid (185mg).

Example K41{4′-Cyano-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-cyano-biphenyl-4-yl)-carbamic acid tert.-butylester (Example G40) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)according to the general procedure K. Obtained as a yellow solid (228mg).

Example K42{4′-Fluoro-3-[3-(3-nitro-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) and2,2-dimethyl-6-(3-nitro-phenyl)-[1,3]dioxin-4-one (Example J12)according to the general procedure K. Obtained as a light yellow solid(1.01 g).

Example K43{4-(4-Fluoro-phenylethynyl)-2-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G33) and6-(2-imidazol-1-yl-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxin-4-one (ExampleJ14) according to the general procedure K. Obtained as a brown solid(284 mg).

MS (ISP) 540 [(M+H)⁺]; mp 169° C.

Example K44{4′-Fluoro-3-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) and6-(2-imidazol-1-yl-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxin-4-one (ExampleJ14) according to the general procedure K. Obtained as a brown solid(361 mg).

MS (ISP) 516 [(M+H)⁺]; mp 124° C. (dec.).

Example K45{2′-Fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)according to the general procedure K. Obtained as a brown solid (352mg).

MS (ISP) 515 [(M+H)⁺]; mp 50–58° C.

Example K46{4-(6-Benzyloxy-pyridin-3-yl)-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(6-benzyloxy-pyridin-3-yl)-phenyl]-carbamicacid tert.-butyl ester (Example G30) (196 mg, 0.5 mmol) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)(229 mg, 0.85 mmol) according to the general procedure K. Obtained as ayellow solid (209 mg).

MS (ISN) 602 [(M−H)⁻]; mp 79–83° C.

Example K47(4′-Fluoro-3-{3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) (362 mg, 1.2 mmol) and3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butylester (Example H7) (300 mg, 1.0 mmol) according to the general procedureK. Obtained as a light yellow solid (392 mg).

MS (ISP) 529 [(M+H)⁺]; mp 124° C.

Example K48{2′-Fluoro-3-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) and6-(2-imidazol-1-yl-pyridin-4-yl)-2,2-dimethyl-[1,3]dioxin-4-one (ExampleJ14) according to the general procedure K. Obtained as an orange solid(103 mg).

MS (ISP) 516 [(M+H)⁺].

Example K49(4-(4-Fluoro-phenylethynyl)-2-{3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G33) (392 mg, 1.2 mmol) and3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butylester (Example H7) (300 mg, 1.0 mmol) according to the general procedureK. Obtained as a yellow solid (407 mg).

MS (ISP) 553 [(M+H)⁺]; mp 166° C.

Example K50{4′-Fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-2′-methyl-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-3′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G41) (158 mg, 0.5 mmol) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)(186 mg, 0.69 mmol) according to the general procedure K. Obtained as anorange oil (168 mg).

MS (ISP) 529 [(M+H)⁺].

Example K51{4′-Fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-2′-methoxymethoxy-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from(3-amino-4′-fluoro-2′-methoxymethoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G42) (181 mg, 0.5 mmol) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)(135 mg, 0.5 mmol) according to the general procedure K. Obtained as ayellow amorphous substance (221 mg).

MS (ISN) 573 [(M−H)⁻].

Example K52(2′-Fluoro-3-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) (362 mg, 1.2 mmol) and3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butylester (Example H8) (300 mg, 1.0 mmol) according to the general procedureK. Obtained as a yellow amorphous substance (312 mg).

MS (ISP) 529 [(M+H)⁺].

Example K53(4′-Fluoro-3-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) (362 mg, 1.2 mmol) and3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acid tert.-butylester (Example H8) (300 mg, 1.0 mmol) according to the general procedureK. Obtained as a yellow amorphous substance (302 mg).

MS (ISP) 529 [(M+H)⁺].

Example K54{3-[3-(3-Cyano-thiophen-2-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) (302 mg, 1.0 mmol) and6-(3-cyano-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J3)(250 mg, 1.06 mmol) according to the general procedure K. Obtained as alight yellow solid (251 mg).

MS (ISP) 480 [(M+H)⁺]; mp 156–157° C.

Example K55{3-[3-(3-Cyano-thiophen-2-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and6-(3-cyano-thiophen-2-yl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J3)(280 mg, 1.19 mmol) according to the general procedure K. Obtained as alight yellow solid (446 mg).

MS (ISP) 480 [(M+H)⁺]; mp 63–66° C.

Example K56{4′-Fluoro-3-[3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) and3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl ester (ExampleH15) according to the general procedure K. Obtained as a light yellowsolid (159 mg).

MS (ISN) 515 [(M−H)⁻].

Example K57{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as a light yellow foam(239 mg).

MS (ISP) 474 [(M+H)⁺].

Example K58{2′-Fluoro-3-[3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) and3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl ester (ExampleH15) according to the general procedure K. Obtained as a light red solid(129 mg).

MS (ISP) 517 [(M+H)⁺].

Example K59(3-{3-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4′-fluoro-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) (227 mg, 0.75 mmol) and3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acidtert.-butyl ester (Example H9) (157 mg, 0.5 mmol) according to thegeneral procedure K. Obtained as a yellow amorphous substance (127 mg).

MS (ISP) 543 [(M+H)⁺].

Example K60(2-{3-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4-phenylethynyl-phenyl)-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example G2) (231 mg, 0.75 mmol) and3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acidtert.-butyl ester (Example H9) (157 mg, 0.5 mmol) according to thegeneral procedure K. Obtained as a yellow amorphous substance (140 mg).

MS (ISP) 549 [(M+H)⁺].

Example K61{3-[3-(3-Chloro-thiophen-2-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) (360 mg, 1.2 mmol) and3-(3-chloro-thiophen-2-yl)-3-oxo-propionic acid ethyl ester (ExampleH16) (350 mg, 1.5 mmol) according to the general procedure K. Obtainedas a white-yellow solid (353 mg).

MS (ISP) 489 [(M+H)⁺] and 491 [(M+2+H)⁺]; mp 168–169° C.

Example K62{2′-Fluoro-3-[3-(3-nitro-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) and2,2-dimethyl-6-(3-nitro-phenyl)-[1,3]dioxin-4-one (Example J12)according to the general procedure K. Obtained as a yellow solid (113mg).

MS (ISN) 492 [(M−H)⁻]; mp 167° C.

Example K63{3-[3-(2-Cyano-pyridin-4-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) and3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (ExampleH10) according to the general procedure K. Obtained as a red solid (118mg).

Example K64{3-[3-(2-Cyano-pyridin-4-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) and3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (ExampleH10) according to the general procedure K. Obtained as a white solid(151 mg).

mp 190° C. (dec.).

Example K65{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-3′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-3′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G38) (151 mg, 0.5 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(175 mg, 0.76 mmol) according to the general procedure K. Obtained as anorange solid (141 mg).

MS (ISP) 474 [(M+H)⁺]; mp 148–150° C.

Example K66{3′-Fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-3′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G38) (151 mg, 0.5 mmol) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)(135 mg, 0.5 mmol) according to the general procedure K. Obtained as anorange solid (150 mg).

MS (ISP) 515 [(M+H)⁺]; mp 70–83° C.

Example K67{2-[3-(2-Cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example G2) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acidtert.-butyl ester (Example H10) according to the general procedure K.Obtained as a white solid (174 mg).

mp 189° C. (dec.).

Example K68{2′-Fluoro-3-[3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionic acid tert.-butyl ester(Example H11) (345 mg, 1.2 mmol) according to the general procedure K.Obtained as a yellow amorphous substance (207 mg).

MS (ISP) 516 [(M+H)⁺].

Example K69{3-[3-(5-Cyano-thiophen-2-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and3-(5-cyano-thiophen-2-yl)-3-oxo-propionic acid tert.-butyl ester(Example H17) (276 mg, 1.1 mmol) according to the general procedure K.Obtained as a yellow solid (451 mg).

MS (ISP) 480 [(M+H)⁺]; mp 201° C.

Example K70(3-{3-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-2′-fluoro-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) (333 mg, 1.1 mmol) and3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acidtert.-butyl ester (Example H9) (314 mg, 1.0 mmol) according to thegeneral procedure K. Obtained as a light yellow solid (374 mg).

MS (ISP) 543 [(M+H)⁺]; mp 145° C.

Example K71(2′-Fluoro-3-{3-[3-(2-methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) (303 mg, 1.0 mmol) and3-[3-(2-methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionicacid tert.-butyl ester (Example H12) (512 mg, 1.41 mmol) according tothe general procedure K. Obtained as a light yellow solid (552 mg).

MS (ISN) 589 [(M−H)⁻]; mp 83–86° C.

Example K72{3-[3-(5-Cyano-2-fluoro-phenyl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) (302 mg, 1.0 mmol) and3-(5-cyano-2-fluoro-phenyl)-3-oxo-propionic acid ethyl ester (ExampleH18) (362 mg, 1.5 mmol) according to the general procedure K. Obtainedas a yellow-brown solid (352 mg).

MS (ISP) 492 [(M+H)⁺]; mp 170° C.

Example K73{3-[3-(2-Cyano-pyridin-4-yl)-3-oxo-propionylamino]-2′,4′-difluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G43) and3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acid tert.-butyl ester (ExampleH10) according to the general procedure K. Obtained as a light brownsolid (207 mg).

MS (ISN) 491 [(M−H)⁻]; mp 160–161° C.

Example K74{2-[3-(2-Cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-isopropyl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-isopropyl-phenyl)-carbamic acid tert.-butylester (Example G47) and 3-(2-cyano-pyridin-4-yl)-3-oxo-propionic acidtert.-butyl ester (Example H10) according to the general procedure K.Obtained as a light brown solid (183 mg).

MS (ISN) 421 [(M−H)⁻]; mp 163–165° C.

Example K75(2′-Fluoro-3-{3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) (151 mg, 0.5 mmol) and3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionic acidtert.-butyl ester (Example H20) (154 mg, 0.5 mmol) according to thegeneral procedure K. Obtained as a yellow amorphous substance (157 mg).

MS (ISN) 534 [(M−H)⁻].

Example K76(4′-Fluoro-3-{3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) (151 mg, 0.5 mmol) and3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionic acidtert.-butyl ester (Example H20) (154 mg, 0.5 mmol) according to thegeneral procedure K. Obtained as a yellow amorphous substance (225 mg).

MS (ISN) 534 [(M−H)⁻].

Example K77{2′-Fluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) (152 mg, 0.5 mmol) and3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester(Example H2) (200 mg, 0.77 mmol) according to the general procedure K.Obtained as a yellow oil (191 mg).

MS (ISP) 516 [(M+H)⁺].

Example K78{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-cyclopropyl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-cyclopropyl-phenyl)-carbamic acid tert.-butylester (Example G48) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as a light brown solid(92 mg).

MS (EI) 419 (M⁺).

Example K79{2-[3-(2-Cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-cyclopropyl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-cyclopropyl-phenyl)-carbamic acid tert.-butylester (Example G48) and4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-pyridine-2-carbonitrile(Example J16) according to the general procedure K. Obtained as a lightbrown solid (148 mg).

MS (ISP) 421 [(M+H)⁺].

Example K80{4-Cyclopropyl-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-cyclopropyl-phenyl)-carbamic acid tert.-butylester (Example G48) and6-(3-imidazol-1-yl-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J10)according to the general procedure K. Obtained as a light yellow solid(79 mg).

MS (ISP) 461 [(M+H)⁺].

Example K81{4′-Fluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) (152 mg, 0.5 mmol) and3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester(Example H2) (200 mg, 0.77 mmol) according to the general procedure K.Obtained as a yellow oil (107 mg).

MS (ISP) 516 [(M+H)⁺].

Example K82{4-(4-Fluoro-phenylethynyl)-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G33) (163 mg, 0.5 mmol) and3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester(Example H2) (181 mg, 0.7 mmol) according to the general procedure K.Obtained as a yellow oil (107 mg).

MS (ISP) 540 [(M+H)⁺].

Example K83{4′-Fluoro-3-[3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) (151 mg, 0.5 mmol) and3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionic acid tert.-butyl ester(Example H19) (235 mg, 0.8 mmol) according to the general procedure K.Obtained as an orange oil (162 mg).

MS (ISP) 522 [(M+H)⁺].

Example K84(4′-Fluoro-3-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) (151 mg, 0.5 mmol) and3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butylester (Example H14) (190 mg, 0.63 mmol) according to the generalprocedure K. Obtained as an off-white solid (86 mg).

MS (ISP) 530 [(M+H)⁺]; mp 100–101° C.

Example K85{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-2′,4′-difluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G43) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as an orange oil (95 mg).

MS (ISP) 492 [(M+H)⁺].

Example K86{2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-isopropyl-phenyl}-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-isopropyl-phenyl)-carbamic acid tert.-butylester (Example G47) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. Obtained as a light red solid (100mg).

MS (ISP) 422 [(M+H)⁺]; mp 179–180° C.

Example K87(4′-Fluoro-3-{3-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G39) and3-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionic acidtert.-butyl ester (Example H13) according to the general procedure K.Obtained as a light yellow oil (181 mg).

MS (ISP) 561 [(M+H)⁺].

Example K88(4-Isopropyl-2-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamicacid tert.-butyl ester

Prepared from (2-amino-4-isopropyl-phenyl)-carbamic acid tert.-butylester (Example G47) and2,2-dimethyl-6-[3-(2-methyl-imidazol-1-yl)-phenyl]-[1,3]dioxin-4-one(Example J15) according to the general procedure K. Obtained as a yellowoil (186 mg).

MS (ISP) 477 [(M+H)⁺].

Example K89(2′,4′-Difluoro-3-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G43) and2,2-dimethyl-6-[3-(2-methyl-imidazol-1-yl)-phenyl]-[1,3]dioxin-4-one(Example J15) according to the general procedure K. Obtained as a yellowoil (145 mg).

MS (ISP) 547 [(M+H)⁺].

Example K90{2′,4′-Difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′,4′-difluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G43) and3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester(Example H2) according to the general procedure K. Obtained as a lightyellow oil (164 mg).

MS (ISP) 534 [(M+H)⁺].

Example K91{2′-Fluoro-3-[3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) (151 mg, 0.5 mmol) and3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionic acid tert.-butyl ester(Example H19) (235 mg, 0.8 mmol) according to the general procedure K.Obtained as a white solid (98 mg).

MS (ISP) 522 [(M+H)⁺]; mp 115–130° C.

Example K92{3-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-2′,5′-difluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′,5′-difluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G45) (160 mg, 0.5 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(115 mg, 0.5 mmol) according to the general procedure K. Obtained as anamorphous white substance (110 mg).

MS (ISN) 490 [(M−H)⁻].

Example K93{2′,5′-Difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′,5′-difluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G45) (160 mg, 0.5 mmol) and3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester(Example H2) (130 mg, 0.5 mmol) according to the general procedure K.Obtained as an amorphous off-white substance (129 mg).

MS (ISN) 532 [(M−H)⁻].

Example K94(2′-Fluoro-3-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′-fluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G37) (151 mg, 0.5 mmol) and3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionic acid tert.-butylester (Example H14) (190 mg, 0.63 mmol) according to the generalprocedure K. Obtained as a white solid (213 mg).

MS (ISN) 528 [(M−H)⁻]; mp 158–160° C.

Example K95{2′,3′-Difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester

Prepared from (3-amino-2′,3′-difluoro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G49) (160 mg, 0.5 mmol) and3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionic acid ethyl ester(Example H2) (130 mg, 0.5 mmol) according to the general procedure K.Obtained as an amorphous yellow substance (166 mg).

MS (ISP) 534 [(M+H)⁺].

Example K96[2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-(2,4-difluoro-phenylethynyl)-phenyl]-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(2,4-difluoro-phenylethynyl)-phenyl]-carbamicacid tert.-butyl ester (Example G35) (172 mg, 0.5 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(126 mg, 0.55 mmol) according to the general procedure K. Obtained as anorange oil (198 mg).

MS (ISP) 516 [(M+H)⁺].

Example K97[2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-(2-fluoro-phenylethynyl)-phenyl]-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(2-fluoro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G34) (163 mg, 0.5 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(126 mg, 0.55 mmol) according to the general procedure K. Obtained as abrown solid (143 mg).

MS (ISN) 496 [(M−H)⁻]; mp 216–217° C.

Example K98[2-[3-(3-Cyano-phenyl)-3-oxo-propionylamino]-4-(4-fluoro-phenylethynyl)-phenyl]-carbamicacid tert.-butyl ester

Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G33) (245 mg, 0.75 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(190 mg, 0.825 mmol) according to the general procedure K. Obtained as ayellow oil (318 mg).

MS (ISN) 496 [(M−H)⁻].

General Procedure M (Synthetic Scheme B)

Preparation of 4,8-diaryl-1,3-dihydro-benzo[b][1,4]diazepin-2-ones,4-aryl-8-aroyl-1,3-dihydro-benzo[b][1,4]diazepin-2-ones or4-aryl-8-arylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-ones

A suspension of the{2-[3-aryl-3-oxo-propionylamino]-4-aryl-phenyl}-carbamic acidtert.-butyl ester or{2-[3-aryl-3-oxo-propionylamino]-4-arylethynyl-phenyl}-carbamic acidtert.-butyl ester (1.0 mmol) in CH₂Cl₂ (5 mL) [anisole or1,3-dimethoxybenzene (5 to 25 mmol) can be added if necessary] wastreated with TFA (0.5–5.0 mL) at 0° C. and stirring was continued at 23°C. until tlc indicated complete consumption of the starting material.The solvent was removed in vacuum, the residue treated with littleether, whereupon it crystallized. The solid was stirred with sat.NaHCO₃-sol., filtered, washed with H₂O and ether or mixtures ofether/hexane and was dried to give the title compound, which ifnecessary can be purified by crystallization fromTHF/CH₂Cl₂/ether/hexane.

Example 13-(7-Iodo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-iodo-phenyl}-carbamicacid tert.-butyl ester (Example K1) (1.15 g, 2.3 mmol) by treatment withTFA in CH₂Cl₂ according to the general procedure M. Obtained as a yellowsolid (880 mg).

MS (EI) 387 (M⁺); mp 198–200° C. (dec.)

Example 23-(4-Oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamicacid tert.-butyl ester (Example K2) (230 mg, 0.48 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as alight yellow solid (135 mg).

MS (EI) 361 (M⁺); mp 245° C. (dec.)

Example 33-(4-Oxo-7-p-tolylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from (2-amino-4-p-tolylethynyl-phenyl)-carbamic acidtert.-butyl ester (Example G3) (161 mg, 0.5 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(183 mg, 0.6 mmol) according to the general procedure K. Obtained as alight yellow solid (228 mg). This material was deprotected and cyclizedby treatment with TFA in CH₂Cl₂ according to the general procedure M.obtained as a light yellow solid (86 mg).

MS (EI) 375 (M⁺); mp 236–239° C. (dec.).

Example 43-[7-(2-Chloro-phenylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from [2-amino-4-(2-chloro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G4) (172 mg, 0.5 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(230 mg, 0.75 mmol, 75% pure) according to the general procedure K.Obtained as a yellow solid (321 mg). This material was deprotected andcyclized by treatment with TFA in CH₂Cl₂ according to the generalprocedure M. Obtained as a light yellow solid (148 mg).

MS (EI) 395 (M⁺) and 397 [(M+2)⁺]; mp 239–240° C. (dec.).

Example 54-(3-Chloro-phenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example G2) and6-(3-chloro-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J6)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as an orange solid (155 mg).

MS (EI): 370 (M⁺)

Example 63-[7-(4-Methoxy-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4′-methoxy-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K3) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow powder(122 mg).

MS (ISP) 368 [(M+H)⁺]; mp 236–237° C. (dec.).

Example 73-(4-Oxo-7-thiophen-3-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-thiophen-3-yl-phenyl}-carbamicacid tert.-butyl ester (Example K4) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a beige solid (54 mg).

MS (EI) 343 (M⁺); mp 238–243° C. (dec.).

Example 83-(7-Furan-2-yl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-furan-2-yl-phenyl}-carbamicacid tert.-butyl ester (Example K5) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a brown powder (73mg).

MS (EI) 327 (M⁺); mp 205–210° C. (dec.).

Example 93-[7-(4-Ethyl-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from (3-amino-4′-ethyl-biphenyl-4-yl)-carbamic acid tert.-butylester (Example G8) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a beige solid (67 mg).

MS (EI) 365 (M⁺); mp 225–229° C. (dec.).

Example 103-(4-Oxo-7-phenyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K6) (268 mg, 0.59 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as awhite solid (188 mg).

MS (EI) 337 (M⁺); mp 238–240° C. (dec.).

Example 114-(3-Iodo-phenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2-[3-(3-iodo-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamicacid tert.-butyl ester (Example K7) (871 mg, 1.5 mmol) by treatment withTFA in CH₂Cl₂ according to the general procedure M. Obtained as a lightyellow solid (542 mg).

MS (EI) 462 (M⁺); mp 227–229° C. (dec.).

Example 128-Phenylethynyl-4-pyridin-4-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example G2) and 2,2-dimethyl-6-pyridin-4-yl-[1,3]dioxin-4-one(Example J9) according to the general procedure K. The obtained materialwas deprotected and cyclized by treatment with TFA in CH₂Cl₂ accordingto the general procedure M. Obtained as a brown solid (50 mg).

MS (EI) 337 (M⁺); mp 198–200° C. (dec.).

Example 133-[7-(2-Methoxy-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from (3-amino-2′-methoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G10) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a light green powder (30 mg).

MS (EI) 367 (M⁺)

Example 143-(7-Furan-3-yl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-furan-3-yl-phenyl}-carbamicacid tert.-butyl ester (Example K9) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow powder(73 mg).

MS (EI) 327 (M⁺); mp 228–233° C. (dec.).

Example 153-[7-(4-Chloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from (3-amino-4′-chloro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G12) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a yellow powder (79 mg).

MS (EI) 371 (M⁺); mp 244–250° C. (dec.).

Example 163-[7-(4-Chloro-phenylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from [2-amino-4-(4-chloro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G13) (187 mg, 0.5 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(184 mg, 0.6 mmol) according to the general procedure K. The obtainedmaterial (234 mg) was deprotected and cyclized by treatment with TFA inCH₂Cl₂ according to the general procedure M. Obtained as a light yellowpowder (93 mg). MS (EI) 395 (M⁺) and 397 [(M+2)⁺]; mp 237–240° C.(dec.).

Example 178-Phenyl-4-thiophen-2-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester(Example G9) (69 mg, 0.243 mmol) and2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (Example J1) (54 mg,0.257 mmol) according to the general procedure K. The obtained materialwas deprotected and cyclized by treatment with TFA in CH₂Cl₂ accordingto the general procedure M. Obtained as a brown solid (46 mg).

MS (ISP) 319 [(M+H)⁺].

Example 188-Phenylethynyl-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example G2) and2,2-dimethyl-6-(3-trifluoromethoxy-phenyl)-[1,3]dioxin-4-one (ExampleJ8) according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a yellow solid (157 mg).

MS (EI) 404 (M⁺).

Example 194-(3-Chloro-phenyl)-8-phenyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester(Example G9) (284 mg, 1.0 mmol) and6-(3-Chloro-phenyl)-2,2-dimethyl-[1,3]dioxin-4-one (Example J6) (358 mg,1.2 mmol) according to the general procedure K. The obtained material(339 mg) was deprotected and cyclized by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (188mg).

MS (EI) 346 (M⁺) and 348 [(M+2)⁺]; mp 208° C. (dec.).

Example 203-(7-Naphthalen-1-yl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-naphthalen-1-yl-phenyl}-carbamicacid tert.-butyl ester (Example K10) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow powder(41 mg).

MS (ISP) 388 [(M+H)⁺]; mp 240–245° C. (dec.)

Example 213-(4-Oxo-7-thiazol-2-ylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-thiazol-2-ylethynyl-phenyl}-carbamicacid tert.-butyl ester (Example K11) (119 mg, 0.24 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as ayellow solid (36 mg).

MS (EI) 368 (M⁺); mp 230° C. (dec.).

Example 223-(4-Oxo-7-p-tolyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from (3-amino-4′-methyl-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G16) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a white solid (76 mg).

MS (ISP) 352 [(M+H)⁺]; mp 242–245° C. (dec.).

Example 234-(3-Chloro-thiophen-2-yl)-8-pyridin-2-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-4-pyridin-2-yl-phenyl}-carbamicacid tert.-butyl ester (Example K12) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light brown powder(51 mg).

MS (EI) 353 (M⁺); mp 220–225° C. (dec.).

Example 243-(4-Oxo-7-thiophen-2-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from (2-amino-4-thiophen-2-yl-phenyl)-carbamic acid tert.-butylester (Example G18) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a light yellow solid (108 mg).

MS (EI) 343 (M⁺); mp>250° C. (dec.).

Example 258-Iodo-4-thiophen-2-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from (2-amino-4-iodo-phenyl)-carbamic acid tert.-butyl ester(Example G1) and 2,2-dimethyl-6-thiophen-2-yl-[1,3]dioxin-4-one (ExampleJ1) according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a yellow solid (30 mg).

MS (EI) 368 (M⁺); mp>260° C.

Example 263-(4-Oxo-7-pyridin-2-ylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from (2-amino-4-pyridin-2-ylethynyl-phenyl)-carbamic acidtert.-butyl ester (Example G19) (124 mg, 0.4 mmol) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)(147 mg, 0.48 mmol) according to the general procedure K. The obtainedmaterial (199 mg) was deprotected and cyclized by treatment with TFA inCH₂Cl₂ according to the general procedure M. Obtained as a yellow solid(124 mg).

MS (EI) 362 (M⁺); mp 229–231° C. (dec.).

Example 274-(3-Methoxy-phenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example G2) and2,2-dimethyl-6-(3-methoxy-phenyl)-[1,3]dioxin-4-one (Example J11)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a light yellow solid (131 mg).

MS (EI) 366 (M⁺).

Example 283-(4-Oxo-7-pyridin-2-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-pyridin-2-yl-phenyl}-carbamicacid tert.-butyl ester (Example K13) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a brown powder (29mg).

MS (EI) 338 (M⁺); mp 243–244° C. (dec.).

Example 298-Phenyl-4-thiophen-3-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from[3-(3-oxo-3-thiophen-3-yl-propionylamino)-biphenyl-4-yl]-carbamic acidtert.-butyl ester (Example K14) (110 mg, 0.25 mmol) by treatment withTFA in CH₂Cl₂ according to the general procedure M. Obtained as a lightyellow solid (53 mg).

MS (EI) 318 (M⁺); mp 233° C. (dec.).

Example 303-(4-Oxo-7-m-tolyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-3′-methyl-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K15) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow powder(145 mg).

MS (ISP) 352 [(M+H)⁺]; mp 248–251° C. (dec.).

Example 313-[7-(3,4-Dichloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from (3-amino-3′,4′-dichloro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G21) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a light yellow solid (150 mg).

MS (EI) 405 (Mt); mp 252–255° C. (dec.).

Example 328-Phenyl-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from (3-amino-biphenyl-4-yl)-carbamic acid tert.-butyl ester(Example G9) (284 mg, 1.0 mmol) and2,2-dimethyl-6-(3-trifluoromethyl-phenyl)-[1,3]dioxin-4-one (Example J5)(408 mg, 1.2 mmol) according to the general procedure K. The obtainedmaterial (392 mg) was deprotected and cyclized by treatment with TFA inCH₂Cl₂ according to the general procedure M. Obtained as a yellow solid(238 mg).

MS (EI) 380 (M⁺); mp 210° C. (dec.).

Example 333-[7-(2-Chloro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from (3-amino-2′-chloro-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G22) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a white powder (43 mg).

MS (ISP) 372 [(M+H)⁺]; mp 240–244° C. (dec.).

Example 344-(3-Chloro-thiophen-2-yl)-8-o-tolyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{3-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-2′-methyl-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K16) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow powder(60 mg).

MS (ISP) 366 (M⁺) and 368 [(M+2)⁺]; mp 247–248° C. (dec.).

Example 358-Benzoyl-4-(3-chloro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4-benzoyl-2-[3-(3-chloro-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K17) (193 mg, 0.39 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as alight yellow solid (93 mg).

MS (EI) 374 (M⁺) and 376 [(M+2)⁺]; mp 199–202° C. (dec.).

Example 363-(7-Benzoyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{4-benzoyl-2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K18) (263 mg, 0.54 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as anorange solid (77 mg).

MS (EI) 365 (M⁺); mp 207° C. (dec.).

Example 378-Benzoyl-4-thiophen-2-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from[4-benzoyl-2-(3-oxo-3-thiophen-2-yl-propionylamino)-phenyl]-carbamicacid tert.-butyl ester (Example K19) (54 mg, 0.12 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as ayellow solid (8 mg).

MS (EI) 346 (M⁺).

Example 384-(3-Chloro-thiophen-2-yl)-8-phenyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{3-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K20) (100 mg, 0.21 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as ayellow solid (93 mg).

MS (EI) 352 (M⁺) and 354 [(M+2)⁺]; mp 228° C. (dec.).

Example 393-[7-(3-Methoxy-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-3′-methoxy-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K21) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow powder(118 mg).

MS (ISP) 368 [(M+H)⁺]; mp 240–243° C. (dec.).

Example 403-(4-Oxo-7-pyridin-3-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from (2-amino-4-pyridin-3-yl-phenyl)-carbamic acid tert.-butylester (Example G26) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a beige powder (161 mg).

MS (EI) 338 (M⁺); mp 210–214° C. (dec.).

Example 418-(6-Oxo-1,6-dihydro-pyridin-3-yl)-4-thiophen-2-yl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from[5-(6-oxo-1,6-dihydro-pyridin-3-yl)-2-(3-oxo-3-thiophen-2-yl-propionylamino)-phenyl]-carbamicacid tert.-butyl ester (Example K22) (127 mg, 0.28 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as ayellow solid (57 mg).

MS (ISP) 336 [(M+H)⁺]; mp>250° C.

Example 428-(6-Benzyloxy-pyridin-3-yl)-4-(3-trifluoromethyl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4-(6-benzyloxy-pyridin-3-yl)-2-[3-oxo-3-(3-trifluoromethyl-phenyl)-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K 23) (198 mg, 0.33 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as ayellow solid (49 mg).

MS (ISP) 488 [(M+H)⁺]; mp 195° C. (dec.).

Example 433-[4-Oxo-7-(4-trifluoromethoxy-phenyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4′-trifluoromethoxy-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K24) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow powder(23 mg).

MS (EI) 421 (M⁺); mp 237–241° C. (dec.).

Example 443-(4-Oxo-7-pyridin-4-yl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from (2-amino-4-pyridin-4-yl-phenyl)-carbamic acid tert.-butylester (Example G28) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a red-brown solid (25 mg).

MS (EI) 338 (M⁺); mp>200° C. (dec.).

Example 453-[7-(1-Benzenesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile[prepared from4-{4-tert.-butoxycarbonylamino-3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert.-butyl ester (Example K25) (690 mg, 1.23 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as abrown solid (309 mg)] (56 mg, 0.164 mmol) and benzenesulfonyl chloride(0.164 mmol) in THF (2 mL) at 23° C. Obtained as a brown solid (40 mg).

MS (ISP) 483 [(M+H)⁺]; mp 92–95° C. (dec.).

Example 463-[7-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile[prepared from4-{4-tert.-butoxycarbonylamino-3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert.-butyl ester (Example K25) (690 mg, 1.23 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as abrown solid (309 mg)] (60 mg, 0.175 mmol), methanesulfonyl chloride(0.014 mL, 0.175 mmol) and Et₃N (0.025 mL, 0.175 mmol) in THF (3 mL) at23° C. Obtained as an orange solid (35 mg).

MS (ISP) 421 [(M+H)⁺]; mp 211–213° C. (dec.).

Example 473-[7-(1-Acetyl-1,2,3,6-tetrahydro-pyridin-4-yl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-yl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile[prepared from4-{4-tert.-butoxycarbonylamino-3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-phenyl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert.-butyl ester (Example K25) (690 mg, 1.23 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as abrown solid (309 mg)] (54 mg, 0.158 mmol) and Ac₂O (0.017 mL, 0.173mmol) in THF (3 mL) at 23° C. Obtained as an orange solid (65 mg).

MS (EI) 384 (M⁺); mp 220–222° C. (dec.).

Example 488-(6-Benzyloxy-pyridin-3-yl)-4-(3-chloro-thiophen-2-yl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4-(6-benzyloxy-pyridin-3-yl)-2-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K26) (172 mg, 0.3 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as ayellow solid (38 mg).

MS (ISP) 460 [(M+H)⁺]; mp 213–215° C. (dec.).

Example 493-[7-(4-Methoxy-phenylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from3-(7-iodo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile(Example 1) (290 mg, 0.75 mmol) and 4-methoxy-phenylacetylene (350 mg,1.57 mmol) according to the general procedure F. Obtained as a lightyellow solid (172 mg).

MS (EI) 391 (M⁺); mp 234–235° C. (dec.).

Example 503-(4-Oxo-7-thiophen-2-ylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from3-(7-iodo-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile(Example 50) (185 mg, 0.48 mmol) and 2-ethynylthiophene (78 mg, 0.72mmol) [prepared from 2-thiophenecarboxaldehyde according to J. Org.Chem. 1982, 47, 2201–2204] according to the general procedure F.Obtained as a light yellow solid (146 mg).

MS (EI) 367 (M⁺); mp 235–238° C. (dec.).

Example 513-[7-(2,3-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′,3′-difluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K8) (35 mg, 0.07 mmol) by treatment withTFA in CH₂Cl₂ according to the general procedure M. Obtained as a greysolid (23 mg).

MS (ISP) 374 [(M+H)⁺]; mp 240° C.

Example 524-(3-Imidazol-1-yl-phenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamicacid tert.-butyl ester (Example K27) (170 mg, 0.33 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as abrown solid (64 mg).

MS (EI) 402 (M⁺); mp 193–196° C.

Example 533-(7-Benzofuran-2-yl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{4-benzofuran-2-yl-2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K28) (255 mg, 0.51 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as ayellow solid (260 mg).

MS (EI) 377 (M⁺); mp>250° C.

Example 543-(7-Biphenyl-4-yl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-[1,1′;4′,1″]terphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K29) (135 mg, 0.25 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as alight yellow solid (100 mg).

MS (EI) 413 (M⁺); mp 251–253° C.

Example 553-[4-Oxo-7-(4-trifluoromethoxy-phenylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from[2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-(4-trifluoromethoxy-phenylethynyl)-phenyl]-carbamicacid tert.-butyl ester (Example K30) (170 mg, 0.3 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as abeige solid (112 mg).

MS (EI) 445 (M⁺); mp 239–241° C.

Example 564-(3-Nitro-phenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2-[3-(3-nitro-phenyl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamicacid tert.-butyl ester (Example K31) (970 mg, 1.94 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as alight yellow solid (631 mg).

MS (EI) 381 (M⁺); mp 228–229° C.

Example 573-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K32) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as an orange solid (141mg).

MS (EI) 355 (M⁺).

Example 588-(4-Fluoro-phenylethynyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4-(4-fluoro-phenylethynyl)-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K33) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a beige solid (89 mg).

MS (EI) 420 (M⁺); mp 216–218° C.

Example 594-(3-Imidazol-1-yl-phenyl)-8-phenyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K34) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(125 mg).

MS (EI) 378 (M⁺); mp 201–205° C.

Example 608-(4-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K35) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as an orange solid (261mg).

MS (EI) 396 (M⁺).

Example 614-(3-Imidazol-1-yl-phenyl)-8-(4-methoxy-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from (3-amino-4′-methoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example K36) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(100 mg). MS (EI) 408 (M⁺); mp 207–208° C.

Example 628-(4-Fluoro-phenylethynyl)-4-(3-[1,2,4]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4-(4-fluoro-phenylethynyl)-2-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K37) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (156mg).

MS (EI) 421 (M⁺); mp 217–218° C.

Example 638-(2-Fluoro-phenylethynyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4-(2-fluoro-phenylethynyl)-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K38) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (99mg).

MS (EI) 420 (M⁺); mp 201–203° C.

Example 648-(4-Fluoro-phenyl)-4-(3-[1,2,4]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4′-fluoro-3-[3-oxo-3-(3-[1,2,4]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K39) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(115 mg).

MS (EI) 397 (M⁺); mp 241–245° C.

Example 653-[7-(4-Cyano-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from{4′-cyano-3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K40) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(102 mg).

MS (EI) 362 (M⁺); mp 240° C. (dec.).

Example 664-[2-(3-Imidazol-1-yl-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-yl]-benzonitrile

Prepared from{4′-cyano-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert-butyl ester (Example K41) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(128 mg).

MS (EI) 403 (M⁺); mp 209–213° C. (dec.).

Example 678-(4-Fluoro-phenyl)-4-(3-nitro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4′-fluoro-3-[3-(3-nitro-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K42) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(719 mg).

MS (ISP) 376 [(M+H)⁺]; mp 220–226° C. (dec.).

Example 688-(4-Fluoro-phenylethynyl)-4-(2-imidazol-1-yl-pyridin-4-yl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4-(4-fluoro-phenylethynyl)-2-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K43) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light brown solid(189 mg).

MS (ISP) 422 [(M+H)⁺]; mp 206° C. (dec.).

Example 698-(4-Fluoro-phenyl)-4-(2-imidazol-1-yl-pyridin-4-yl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4′-fluoro-3-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K43) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light brown solid(209 mg).

MS (ISP) 398 [(M+H)⁺]; mp 213° C. (dec.).

Example 704-(3-Amino-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from8-(4-fluoro-phenyl)-4-(3-nitro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 67) by catalytic hydrogenation with Raney-Ni according to thegeneral procedure G (method a). Obtained as a light yellow solid (16mg).

MS (ISP) 346 [(M+H)⁺]; mp 210–217° C. (dec.).

Example 718-(2-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K45) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(176 mg).

MS (ISP) 397 [(M+H)⁺]; mp 179–182° C.

Example 72N-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-acetamide

Prepared from4-(3-amino-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 70) by treatment with Ac₂O in HOAc at 80° C. Obtained as alight yellow solid (9 mg).

MS (EI) 387 (M⁺).

Example 73N-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-methanesulfonamide

Prepared from4-(3-amino-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 70) by treatment with methanesulfonyl chloride and Et₃N in THFat 23° C. Obtained as a light yellow solid (24 mg).

MS (ISP) 424 [(M+H)⁺]; mp 232–235° C.

Example 748-(6-Benzyloxy-pyridin-3-yl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4-(6-benzyloxy-pyridin-3-yl)-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K46) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(75 mg).

MS (ISP) 486 [(M+H)⁺]; mp 225–231° C.

Example 754-(3-Imidazol-1-yl-phenyl)-8-(6-oxo-1,6-dihydro-pyridin-3-yl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from8-(6-benzyloxy-pyridin-3-yl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 74) by catalytic hydrogenation with Raney-Ni according to thegeneral procedure G (method a). Obtained as a light yellow solid (17mg).

MS (ISP) 396 [(M+H)⁺].

Example 768-(4-Fluoro-phenyl)-4-[3-(4-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(4′-fluoro-3-{3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K47) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(196 mg).

MS (EI) 410 (M⁺); mp 215° C.

Example 778-(2-Fluoro-phenyl)-4-(2-imidazol-1-yl-pyridin-4-yl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2′-fluoro-3-[3-(2-imidazol-1-yl-pyridin-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K48) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light brown solid(32 mg).

MS (EI) 397 (M⁺).

Example 788-(4-Fluoro-phenylethynyl)-4-[3-(4-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(4-(4-fluoro-phenylethynyl)-2-{3-[3-(4-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamicacid tert.-butyl ester (Example K49) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(122 mg).

MS (EI) 434 (M⁺); mp 210° C.

Example 798-(4-Fluoro-2-methyl-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-2′-methyl-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K50) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a beige solid (82 mg).

MS (EI) 410 (M⁺); mp 170–172° C.

Example 808-(4-Fluoro-2-hydroxy-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-2′-methoxymethoxy-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K51) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(13 mg).

MS (ISP) 413 [(M+H)⁺]; mp 220° C.

Example 818-(2-Fluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(2′-fluoro-3-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K52) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (174mg).

MS (ISP) 411 [(M+H)⁺]; mp 187° C.

Example 828-(4-Fluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(4′-fluoro-3-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K53) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (178mg).

MS (ISP) 411 [(M+H)⁺]; mp 227° C.

Example 832-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]-thiophene-3-carbonitrile

Prepared from{3-[3-(3-cyano-thiophen-2-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K54) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as an orange solid (209mg).

MS (EI) 361 (M⁺); mp 239–240° C.

Example 842-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]-thiophene-3-carbonitrile

Prepared from{3-[3-(3-cyano-thiophen-2-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K55) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (258mg).

MS (EI) 361 (M⁺); mp 238–240° C.

Example 858-(4-Fluoro-phenyl)-4-(3-tetrazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4′-fluoro-3-[3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K56) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(54 mg).

MS (EI) 398 (M⁺).

Example 863-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K57) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(128 mg).

MS (EI) 355 (M⁺).

Example 878-(4-Fluoro-phenylethynyl)-4-(3-tetrazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from [2-amino-4-(4-fluoro-phenylethynyl)-phenyl]-carbamic acidtert.-butyl ester (Example G33) and3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionic acid ethyl ester (ExampleH15) according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a beige powder (5.5 mg).

MS (EI) 422 (M⁺).

Example 888-(2-Fluoro-phenyl)-4-(3-tetrazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2′-fluoro-3-[3-oxo-3-(3-tetrazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K58) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(31 mg).

MS (EI) 398 (M⁺); mp 179–180° C.

Example 894-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(3-{3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4′-fluoro-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K59) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (54mg).

MS (EI) 424 (M⁺); mp 188° C.

Example 904-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(2-{3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-4-phenylethynyl-phenyl)-carbamicacid tert.-butyl ester (Example K60) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (57mg). MS (EI) 430 (M⁺); mp 134° C. (dec.).

Example 914-(3-Chloro-thiophen-2-yl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{3-[3-(3-chloro-thiophen-2-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K61) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (232mg).

MS (EI) 370 (M⁺); mp 255–256° C.

Example 923-[7-(2-Fluoro-6-methoxy-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from (3-amino-2′-fluoro-6′-methoxy-biphenyl-4-yl)-carbamic acidtert.-butyl ester (Example G44) and3-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-benzonitrile (Example J4)according to the general procedure K. The obtained material wasdeprotected and cyclized by treatment with TFA in CH₂Cl₂ according tothe general procedure M. Obtained as a white solid (47 mg).

MS (EI) 385 (M⁺).

Example 938-(2-Fluoro-phenyl)-4-(3-nitro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2′-fluoro-3-[3-(3-nitro-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K62) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(62 mg).

MS (EI) 375 (M⁺).

Example 944-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile

Prepared from{3-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K63) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as an orange solid (23mg).

MS (EI) 356 (M⁺).

Example 954-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile

Prepared from{3-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K64) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a green solid (40 mg).

MS (EI) 356 (M⁺).

Example 963-[7-(3-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-3′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K65) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (57mg).

MS (EI) 355 (M⁺); mp 232–235° C.

Example 978-(3-Fluoro-phenyl)-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{3′-fluoro-3-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K66) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (69mg).

MS (EI) 396 (M⁺); mp 200–201° C.

Example 984-(4-Oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile

Prepared from{2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-phenylethynyl-phenyl}-carbamicacid tert.-butyl ester (Example K67) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (10mg).

MS (EI) 362 (M⁺).

Example 998-(2-Fluoro-phenyl)-4-(3-[1,2,4]triazol-4-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2′-fluoro-3-[3-oxo-3-(3-[1,2,4]triazol-4-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K68) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(79 mg).

MS (EI) 397 (M⁺); mp 198° C.

Example 1005-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiophene-2-carbonitrile

Prepared from{3-[3-(5-cyano-thiophen-2-yl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K69) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (263mg).

MS (EI) 361 (M⁺); mp>250° C.

Example 1014-[3-(2,4-Dimethyl-imidazol-1-yl)-phenyl]-8-(2-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(3-{3-[3-(2,4-dimethyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-2′-fluoro-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K70) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (92mg).

MS (EI) 424 (M⁺); mp 92° C.

Example 1028-(2-Fluoro-phenyl)-4-[3-(2-methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(2′-fluoro-3-{3-[3-(2-methoxymethylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K71) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(100 mg).

MS (EI) 472 (M⁺); mp 189–190° C.

Example 1034-Fluoro-3-[7-(2-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from{3-[3-(5-cyano-2-fluoro-phenyl)-3-oxo-propionylamino]-2′-fluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K72) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (92mg).

MS (EI) 373 (M⁺); mp 239° C.

Example 1044-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile

Prepared from{3-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-2′,4′-difluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K73) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(24 mg).

MS (ISP) 375 [(M+H)⁺]; mp 250–253° C.

Example 1054-(7-Isopropyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile

Prepared from{2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-isopropyl-phenyl}-carbamicacid tert.-butyl ester (Example K74) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (33mg).

MS (ISP) 305 [(M+H)⁺]; mp 173–178° C.

Example 1068-(2-Fluoro-phenyl)-4-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(2′-fluoro-3-{3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K75) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (75mg).

MS (ISP) 418 [(M+H)⁺]; mp 229° C.

Example 1078-(4-Fluoro-phenyl)-4-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(4′-fluoro-3-{3-[2-(4-methyl-imidazol-1-yl)-thiazol-4-yl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K76) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (101mg).

MS (ISP) 418 [(M+H)⁺]; mp 229° C.

Example 1083-(4-Oxo-7-phenethyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from3-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile(Example 2) by catalytic hydrogenation with Pd/C according to thegeneral procedure G (method a). Obtained as a light yellow solid (156mg).

MS (EI) 365 (M⁺); mp 212–214° C.

Example 1093-(4-Oxo-7-styryl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from3-(4-oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile(Example 2) by catalytic hydrogenation with Lindlar-catalyst in thepresence of 10 eq. cyclohexene according to the general procedure G(method a). Obtained as a light yellow solid (159 mg).

MS (EI) 363 (M⁺); mp 185–188° C.

Example 1108-(2-Fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2′-fluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K77) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(100 mg).

MS (EI) 397 (M⁺); mp 209–212° C.

Example 1113-(7-Cyclopropyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-cyclopropyl-phenyl}-carbamicacid tert.-butyl ester (Example K78) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(44 mg).

MS (ISP) 302 [(M+H)⁺]; mp 204–209° C.

Example 1124-(7-Cyclopropyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-pyridine-2-carbonitrile

Prepared from{2-[3-(2-cyano-pyridin-4-yl)-3-oxo-propionylamino]-4-cyclopropyl-phenyl}-carbamicacid tert.-butyl ester (Example K79) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light brown solid(88 mg).

MS (ISP) 303 [(M+H)⁺]; mp 227–230° C.

Example 1138-Cyclopropyl-4-(3-imidazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4-cyclopropyl-2-[3-(3-imidazol-1-yl-phenyl)-3-oxo-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K80) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light brown solid(41 mg).

MS (ISP) 303 [(M+H)⁺]; mp 198–200° C.

Example 1148-(4-Fluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2′-fluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K81) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(29 mg).

MS (EI) 397 (M⁺); mp 218–220° C.

Example 1158-(4-Fluoro-phenylethynyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4-(4-fluoro-phenylethynyl)-2-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-phenyl}-carbamicacid tert.-butyl ester (Example K82) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(53 mg).

MS (EI) 421 (M⁺); mp 246–248° C.

Example 1168-(4-Fluoro-phenyl)-4-(2-imidazol-1-yl-thiazol-4-yl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{4′-fluoro-3-[3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K83) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light brown solid(64 mg).

MS (ISP) 404 [(M+H)⁺]; mp 214° C.

Example 1178-(4-Fluoro-phenyl)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(4′-fluoro-3-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K84) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(33 mg).

MS (EI) 411 (M⁺); mp>250° C.

Example 1183-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′,4′-difluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K85) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(37 mg).

MS (ISP) 374 [(M+H)⁺].

Example 1193-(7-Isopropyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from{2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-isopropyl-phenyl}-carbamicacid tert.-butyl ester (Example K86) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as an off-white solid (25mg).

MS (ISP) 304 [(M+H)⁺].

Example 1208-(4-Fluoro-phenyl)-4-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(4′-fluoro-3-{3-[3-(2-methylsulfanyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K87) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(104 mg).

MS (ISP) 443 [(M+H)⁺].

Example 1218-Isopropyl-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(4-isopropyl-2-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamicacid tert.-butyl ester (Example K88) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light brown solid(94 mg).

MS (ISP) 359 [(M+H)⁺].

Example 1228-(2,4-Difluoro-phenyl)-4-[3-(2-methyl-imidazol-1-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(2′,4′-difluoro-3-{3-[3-(2-methyl-imidazol-1-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K89) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light brown solid(71 mg).

MS (ISP) 429 [(M+H)⁺].

Example 1238-(2,4-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2′,4′-difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K90) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light brown solid(78 mg).

MS (ISP) 416 [(M+H)⁺].

Example 1248-(2-Fluoro-phenyl)-4-(2-imidazol-1-yl-thiazol-4-yl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2′-fluoro-3-[3-(2-imidazol-1-yl-thiazol-4-yl)-3-oxo-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K91) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(46 mg).

MS (ISP) 404 [(M+H)⁺]; mp 194–197° C.

Example 1253-[7-(2,5-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from{3-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-2′,5′-difluoro-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K92) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(49 mg).

MS (EI) 373 (M⁺); mp 247° C.

Example 1268-(2,5-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2′,5′-difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K93) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(67 mg).

MS (EI) 415 (M⁺); mp 231° C.

Example 1278-(2-Fluoro-phenyl)-4-[3-(3-methyl-isoxazol-5-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from(2′-fluoro-3-{3-[3-(3-methyl-isoxazol-5-yl)-phenyl]-3-oxo-propionylamino}-biphenyl-4-yl)-carbamicacid tert.-butyl ester (Example K94) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(100 mg).

MS (EI) 411 (M⁺); mp 222–224° C.

Example 1287-Methyl-4-[3-(1-methyl-1H-imidazol-2-yl)-phenyl]-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from (2-amino-4-phenylethynyl-phenyl)-carbamic acid tert.-butylester (Example G2) (620 mg, 2.0 mmol) and3-[3-(1-methyl-1H-imidazol-2-yl)-phenyl]-3-oxo-propionic acidtert.-butyl ester (Example H21) (1.26 g, 4.2 mmol) according to thegeneral procedure K. The obtained material was deprotected and cyclizedby treatment with TFA in CH₂Cl₂ according to the general procedure M.Obtained as a light yellow solid (81 mg).

MS (ISP) 417.2 [(M+H)⁺]; mp 202–205° C.

Example 1298-(2,3-Difluoro-phenyl)-4-(3-[1,2,3]triazol-1-yl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from{2′,3′-difluoro-3-[3-oxo-3-(3-[1,2,3]triazol-1-yl-phenyl)-propionylamino]-biphenyl-4-yl}-carbamicacid tert.-butyl ester (Example K95) (118 mg, 0.22 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as ayellow solid (74 mg). mp 230° C.

Example 1303-[7-(2,4-Difluoro-phenylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from[2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-(2,4-difluoro-phenylethynyl)-phenyl]-carbamicacid tert.-butyl ester (Example K96) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(87 mg).

MS (EI) 397 (M⁺); mp 240–246° C.

Example 1313-[7-(2-Fluoro-phenylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from[2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-(2-fluoro-phenylethynyl)-phenyl]-carbamicacid tert.-butyl ester (Example K97) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a yellow solid (82mg).

MS (EI) 379 (M⁺); mp 213–214° C.

Example 1328-Phenylethynyl-4-(3-trimethylsilanylethynyl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 11) (231 mg, 0.5 mmol) and trimethylsilylacetylene (0.4 mL, 1.0mmol) according to the general procedure F. Obtained as a light brownsolid (102 mg).

MS (EI) 432 (M⁺); mp 169–171° C. (dec.).

Example 1334-(3-Ethynyl-phenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from8-phenylethynyl-4-(3-trimethylsilanylethynyl-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 132) (63 mg, 0.146 mmol) by treatment with 1N NaOH (3 drops) inMeOH (3 mL) and THF (0.5 mL) at 23° C. for 2 h. Obtained as a brownsolid (31 mg).

MS (ISP) 361 [(M+H)⁺]; mp>250° C. (dec.).

Example 1343-[7-(3-Hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 11) (194 mg, 0.5 mmol) and 2-methyl-3-butyn-2-ol (105 mg, 1.25mmol) according to the general procedure F. Obtained as a yellow solid(147 mg).

MS (EI) 343 (M⁺); mp 243° C.

Example 1353-[7-(1-Hydroxy-cyclohexylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 11) (308 mg, 0.80 mmol) and 1-ethynyl-1-cyclohexanol (248 mg,2.00 mmol) according to the general procedure F. Obtained as a beigesolid (262 mg).

MS (ISP) 384 [(M+H)⁺]; mp 196° C.

Example 1363-(7-Cyclohex-1-enylethynyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzonitrile

Prepared from3-[7-(1-hydroxy-cyclohexylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile(Example 135) (50 mg, 0.13 mmol) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a light yellow solid(22 mg).

MS (EI) 365 (M⁺); mp 228° C.

Example 1373-[7-(3-Methyl-but-3-en-1-ynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from3-[7-(3-hydroxy-3-methyl-but-1-ynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile(Example 134) (50 mg, 0.15 mmol) by treatment with TFA in CH₂Cl₂according to the general procedure M. Obtained as a sand solid (33 mg).

MS (ISP) 326 [(M+H)⁺]; mp 231° C.

Example 1383-[7-(3,6-Dihydro-2H-pyran-4-ylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from3-[7-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile[prepared from4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 11) (387 mg, 1.0 mmol) and 4-ethynyl-tetrahydro-pyran-4-ol[CAS-No. 57385-16-7] (315 mg, 2.5 mmol) according to the generalprocedure F. Obtained as a yellow solid (296 mg)] (50 mg, 0.13 mmol) bytreatment with TFA in CH₂Cl₂ according to the general procedure M.Obtained as a light yellow solid (16 mg).

MS (EI) 367 (M⁺); mp 238° C.

Example 1394-[2-(3-Cyano-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-ylethynyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert.-butyl ester

Prepared from4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 11) (1.16 g, 3.0 mmol) and4-ethynyl-3,6-dihydro-2H-pyridine-1-carboxylic acid tert.-butyl ester[CAS-No. 177984-28-0] (0.93 g, 4.5 mmol) according to the generalprocedure F. Obtained as a yellow solid (620 mg).

MS (ISP) 467 [(M+H)⁺]; mp 239° C.

Example 1403-[4-Oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from4-[2-(3-cyano-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-7-ylethynyl]-3,6-dihydro-2H-pyridine-1-carboxylicacid tert.-butyl ester (Example 139) (573 mg, 1.13 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as anoff-white solid (434 mg).

MS (ISP) 367 [(M+H)⁺]; mp 184° C.

Example 1413-[7-(1-Acetyl-1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile(Example 140) (55 mg, 0.15 mmol) by treatment with Ac₂O (0.017 mL, 0.165mmol) in THF (3 mL) at 23° C. for 1 h. Obtained as a sand solid (59 mg).

MS (ISP) 409 [(M+H)⁺]; mp 203° C.

Example 1423-[7-(1-Methanesulfonyl-1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile(Example 140) (55 mg, 0.15 mmol) by treatment with methanesulfonylchloride (0.012 mL, 0.15 mmol) and Et₃N (0.021 mL, 0.15 mmol) in THF (3mL) at 23° C. for 23 h. Obtained as a yellow solid (38 mg).

MS (EI) 444 (M⁺); mp 235° C.

Example 1433-{7-[1-(2,2-Dimethyl-propionyl)-1,2,3,6-tetrahydro-pyridin-4-ylethynyl]-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl}-benzonitrile

Prepared from3-[4-oxo-7-(1,2,3,6-tetrahydro-pyridin-4-ylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile(Example 140) (55 mg, 0.15 mmol) by treatment with pivaloyl chloride(0.02 mL, 0.165 mmol) and Et₃N (0.021 mL, 0.15 mmol) in THF (3 mL) at23° C. for 19 h. Obtained as a sand solid (26 mg).

MS (ISP) 451 [(M+H)⁺]; mp 219° C.

Example 1443-[4-Oxo-7-(3-oxo-cyclohex-1-enylethynyl)-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 11) (500 mg, 1.29 mmol) and 3-ethynyl-cyclohex-2-enone [CAS-No.124267-26-1] (310 mg, 2.58 mmol) according to the general procedure F.Obtained as a yellow solid (346 mg).

MS (EI) 379 (M⁺); mp 110° C.

Example 1453-[7-(4-Fluoro-phenylethynyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile

Prepared from[2-[3-(3-cyano-phenyl)-3-oxo-propionylamino]-4-(4-fluoro-phenylethynyl)-phenyl]-carbamicacid tert.-butyl ester (Example K98) (307 mg, 0.62 mmol) by treatmentwith TFA in CH₂Cl₂ according to the general procedure M. Obtained as aeggshell solid (146 mg).

MS (EI) 379 (M⁺); mp 245–246° C.

The following examples relate to the palladium-catalyzed carbonylationof the4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-onein the presence of secondary amines leads directly to the correspondingamides as shown in synthetic scheme H.

General Procedure N

Preparation of4-[3-(Amino-4-carbonyl)-phenyl]-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-onesby Pd-catalyzed carbonylative amination of4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

A solution of4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 11) (1.0 mmol), the secondary amine (5.0 mmol), PPh₃ (6 mol %)or dppp (3 mol %), Pd(OAc)₂ (3 mol %) and Et₃N (2.0 mmol) in DMF (4 mL)was stirred at 23° C. under CO-atmosphere until tlc indicated completeconsumption of the iodide. After dilution with EtOAc, washing with sat.NaHCO₃-sol. and brine, the organic phase was dried over Na₂SO₄. Removalof the solvent left a brown oil, which was purified by silica gel columnchromatography with hexane/EtOAc to give the title compound.

Example 1464-[3-(Morpholine-4-carbonyl)-phenyl]-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 11) (471 mg, 1.02 mmol) and morpholine (0.44 mL, 5.09 mmol)according to the general procedure N. Obtained as a light yellow solid(324 mg).

MS (ISP) 450 [(M+H)⁺]; mp 142–145° C. (dec.).

Example 1474-[3-(4-Methyl-piperazine-1-carbonyl)-phenyl]-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one

Prepared from4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 11) (231 mg, 0.5 mmol) and N-methylpiperazine (0.28 mL, 2.5mmol) according to the general procedure N. Obtained as a light yellowsolid (65 mg).

MS (ISP) 463 [(M+H)⁺]; mp 168–172° C. (dec.).

Example 1483-(4-Oxo-7-phenylethynyl-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl)-benzamide

Prepared from4-(3-iodophenyl)-8-phenylethynyl-1,3-dihydro-benzo[b][1,4]diazepin-2-one(Example 11) (231 mg, 0.5 mmol) and hexamethyldisilazane (0.52 mL, 2.5mmol) according to the general procedure N. Obtained as a yellow solid(104 mg).

MS (EI) 379 (M⁺); mp>250° C. (dec.).

Example 1493-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamide

Preparation of4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamides(according to Pen-Yuan Lin et al. Synthesis 1992, 1219]: To a solutionof hexamethyldisilthiane (1.45 g, 8.0 mmol) in1,3-dimethyl-2-imidazolidinone (8 mL) was added at 23° C. sodiummethoxide (0.31 g, 6.8 mmol). The mixture was stirred for 5 min. and theblue solution formed was then added to a solution of3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile(Example 57) (1.42 g, 4 mmol) in 1,3-dimethyl-2-imidazolidinone (12 mL).The mixture was stirred for 3 h at 23° C. and then poured into water(100 mL). Stirring was continued for 0.5 h and the precipitate wasisolated by filtration and triturated with ethyl acetate (50 mL) to givethe title compound as light yellow solid (1.38 g).

MS (ISN) 387.9 [(M−H)⁻]; mp 267–270° C. (dec.).

Example 1503-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamide

3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile(Example 86) (0.53 g) was subjected in an analogous manner to theprocedure described in Example 149 to give, after trituration of thecrude product with ethyl acetate, the title compound as light yellowsolid (0.46 g).

MS (ISN) 387.9 [(M−H)⁻]; mp 232–234° C. (dec.).

Example 1514-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbothioicacid amide

(Example 94) (0.36 g) was subjected in an analogous manner the proceduredescribed in Example 149 to give, after trituration of the crude productwith acetone, the title compound as light yellow solid (0.33 g).

MS (ISN) 388.9 [(M−H)⁻]; mp 280–283° C. (dec.).

Example 1528-(4-Fluoro-phenyl)-4-[3-(4-methyl-thiazol-2-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

To a suspension of3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamide(Example 149) (97 mg, (0.25 mmol) in ethanol (5 mL) was addedchloroacetone (0.1 mL, 1.25 mmol) and the mixture was heated at reflux.After 1 h and after 5 h of heating, more chloroacetone (2 times 0.1 mL,1.25 mmol) was added. After 20 h the mixture was cooled to 0° C. andstirred for 0.5 h, and the title compound was isolated by filtration aslight yellow solid (61 mg).

MS (ISP) 428.4 [(M+H)⁺]; mp 259–261° C. (dec.).

Example 1532-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylicacid ethyl ester

A mixture of3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamide(Example 149) (39 mg, 0.1 mmol) and ethyl bromopyruvate (29 mg, 0.15mmol) in ethanol (0.5 mL) was heated at reflux for 7 h. The solution wascooled to 0° C., stirred for 0.5 h, and the title compound was isolatedby filtration as light yellow solid (29 mg).

MS (ISN) 484.2 [(M−H)⁻]; mp 236–238° C. (dec.).

Example 1542-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylicacid ethyl ester

3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamide(Example 150) (0.24 g) was subjected in an analogous manner to theprocedure described in Example 153. The reaction mixture was evaporatedin vacuum and the residue was triturated with ethyl acetate to give thetitle compound as light yellow solid (0.29 g).

MS (ISP) 503.4 [(M+NH₄)⁺]; mp 172–175° C.

Example 1552-{4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridin-2-yl}-thiazole-4-carboxylicacid ethyl ester

-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbothioicacid amide (Example 151) (160 mg) was subjected in an analogous mannerto the procedure described in Example 153. The cooled reaction solutionwas diluted with ethyl acetate, washed with NaHCO₃-sol. and with brine,dried over Na₂SO₄ and evaporated in vacuum. The crude product waschromatographed on silica gel using ethyl acetate/hexane (2:1) aseluent, and the purified product was triturated withdichloromethane/diethyl ether to give the title compound as light yellowsolid (40 mg).

MS (ISN) 485.1 [(M−H)⁻]; mp 238–240° C. (dec.).

Example 1568-(4-Fluoro-phenyl)-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

To a solution of2-{3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylicacid ethyl ester (Example 153) (110 mg, 0.23 mmol) in THF (7 mL) wasadded a 3.5 M solution of sodium dihydrido-bis(2-methoxyethoxy)aluminatein toluene (0.66 mL, 2.3 mmol). The raction mixture was stirred at 23°C. for 15 min. and then poured into ice-cold 10% aq. acetic acid. Themixture was extracted with ethyl acetate and the organic layer waswashed successively with H₂O, sat. Na₂CO₃-sol. and brine, dried overNa₂SO₄ and evaporated in vacuum. The residue was triturated with ethylacetate to give the title compound as light yellow solid (48 mg).

MS (ISN) 442.1 [(M−H)⁻]; mp 235–239° C. (dec.).

Example 1578-(2-Fluoro-phenyl)-4-[3-(4-hydroxymethyl-thiazol-2-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

2-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylicacid ethyl ester (Example 154) (97 mg) was subjected in an analogousmanner to the procedure described in Example 156 to give the titlecompound as light yellow solid (30 mg).

MS (ISN) 442.1 [(M−H)⁻]; mp 238–244° C. (dec.).

Example 1588-(4-Fluoro-phenyl)-4-[2-(4-hydroxymethyl-thiazol-2-yl)-pyridin-4-yl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

2-{4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridin-2-yl}-thiazole-4-carboxylicacid ethyl ester (Example 155) (84 mg) was subjected in an analogousmanner to the procedure described in Example 156. The crude product waschromatographed on silica gel using ethyl acetate/hexane (2:1) and ethylacetate as eluent, and the purified product was crystallized from ethylacetate/hexane to give the title compound as light yellow solid (16 mg).

MS (ISP) 445.2 [(M+H)⁺]; mp 225–229° C.

Example 1592-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylicacid

To a solution of2-{3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylicacid ethyl ester (Example 153) (49 mg, 0.1 mmol) in a mixture of MeOH (1mL) and DMSO (1.5 mL) was added 2N KOH (1 mL, 2 mmol). The mixture wasstirred at 23° C. for 0.5 h and then partitioned between ethyl acetateand H₂O. The pH of the aqueous phase was set to 3 by the addition of 3NHCl and then stirred in the ice-bath for 0.5 h. The precipitate wascollected by filtration, triturated with EtOH/Et₂O (1/1) and dried, togive the title compound as light yellow solid (25 mg).

MS (ISN) 456.4 [(M−H)⁻]; mp 286–290° C. (dec.).

Example 1602-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylicacid

2-{3-[7-(2-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylicacid ethyl ester (Example 154) (97 mg) was subjected in an analogousmanner to the procedure described in Example 159 to give the titlecompound as light yellow solid (60 mg).

MS (ISN) 456.2 [(M−H)⁻]; mp 261–263° C. (dec.).

Example 1612-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylicacid (2-hydroxy-ethyl)-amide

A solution of2-{3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-thiazole-4-carboxylicacid ethyl ester (Example 153) (49 mg, 0.1 mmol) in 2-amino-ethanol washeated to 40° C. for 40 min. The cooled solution was partitioned betweenethyl acetate and H₂O and the organic layer was dried over Na₂SO₄ andevaporated in vacuum. The residue was triturated with ethyl acetate togive to give the title compound as light yellow solid (21 mg).

MS (ISP) 518.3 [(M+NH₄)⁺]; mp 238–245° C. (dec.).

Example 1622-{3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-phenyl}-4-methyl-thiazole-5-carboxylicacid (2-hydroxy-ethyl)-amide

A mixture3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-thiobenzamide(Example 149) (78 mg, 0.2 mmol) and ethyl 4-chloro-3-oxo-butanoate (164mg, 1.0 mmol) in ethanol (4 mL) was heated at reflux for 24 h. Thesolution was cooled to 0° C. and stirred for 0.5 h. The crystals wereisolated by filtration and subsequently suspended in 2-amino-ethanol (4mL). The mixture was stirred at 70° C. for 4 h, cooled to 23° C., andpartitioned between ethyl acetate and H₂O. The organic layer was driedover Na₂SO₄ and evaporated in vacuum and the residue was triturated withethyl acetate to give the title compound as light yellow solid (37 mg).

MS (ISP) 515.3 [(M+H)⁺]; mp 248–251° C. (dec.).

Example 1633-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoicacid

To a suspension of3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile(Example 57) (355 mg, 1 mmol) in EtOH (2 mL) was added 2N KOH (5 mL).The mixture was heated at reflux for 3 h, then cooled to 23° C. andpartitioned between ethyl acetate and H₂O. The pH of the aqueous phasewas set to 3 by the addition of 3N HCl, a precipitate being formed. Themixture was stirred in the ice-bath for nn 0.5 h. The crystalline solidwas collected by filtration, triturated with ethyl acetate and dried, togive the title compound as light yellow solid (218 mg).

MS (ISN) 373.3 [(M−H)⁻]; mp 290–296° C. (dec.).*

Example 1644-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carboxylicacid

4-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile(Example 94) (356 mg) was subjected in an analogous manner to theprocedure described in Example 163. The reaction mixture was partitionedbetween ethyl acetate and H₂O, and the pH of the aqueous phase was setto 3 by the addition of 3N HCl, a precipitate being formed. The mixturewas extracted with ethyl acetate and the organic layer was washed withbrine, dried over Na₂SO₄, and evaporated in vacuum. The residue wastriturated with EtOH to give the title compound as yellow solid (190mg).

MS (ISN) 374.2 [(M−H)⁻]; mp 211–213° C. (dec.).

Example 1658-(4-Fluoro-phenyl)-4-[3-(5-methyl-[1,3,4]oxadiazol-2-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

A mixture of3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoicacid hydrazide (Starting material 8a-2) (58 mg, 0.15 mmol) and ethylacetimidate hydrochloride (74 mg, 0.6 mmol) in pyridine (0.6 mL) washeated to 100° C. for 2 h. The mixture was cooled to 23° C., dilutedwith H₂O (30 mL) and stirred for 20 min. The precipitate was collectedby filtration, and the crude product was purified by chromatography onsilica gel using ethyl acetate/hexane (2:1) as eluent. The purifiedproduct was crystallized from Et₂O/hexane to give the title compound aslight yellow solid (28 mg).

MS (ISP) 430.3 [(M+NH₄)⁺]; mp 254–256° C. (dec.).

Starting Material 8a-13-[7-(3-Fluoromethyl-phenyl)-8-methyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoicacid allyl ester

To a solution of3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoicacid (Example 163) (749 mg, 2 mmol) and 1,1,3,3,-tetramethylguanidine(230 mg, 2 mmol) in DMSO (24 mL) was added allyl bromide (242 mg, 2mmol) and the mixture was stirred at 23° C. for 2.5 h. H₂O (100 mL) wasadded and stirring was continued for 20 min. The precipitate wascollected by filtration and triturated with ethyl acetate/Et2O (1:1) togive the title compound as light yellow solid (705 mg).

MS (ISP) 415.2 [(M+H)⁺]; mp 226–228° C.

Starting Material 8a-2

3-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoicacid hydrazide

To a suspension of3-[7-(3-fluoromethyl-phenyl)-8-methyl-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoicacid allyl ester (Starting material 8a-1) (207 mg, 0.5 mmol) in MeOH(3.5 mL) was added hydrazine hydrate (0.25 mL, 5 mmol). The mixture wasstirred at 60° C. for 15 h, then cooled to 23° C. and diluted with H₂O(35 mL). The precipitate was collected by filtration and dried, and thecrude product was purified by chromatography on silica gel using ethylacetate/hexane (1:1) as eluent. The purified product was crystallizedfrom Et₂O/hexane to give the title compound as light yellow solid (64mg).

MS (ISN) 387.0 [(M−H)⁻]; mp 256–258° C. (dec.).

Example 1664-[3-(4,5-Dimethyl-4H-[1,2,4]triazol-3-yl)-phenyl]-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

A mixture of3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoicacid hydrazide (Starting material 8a-2)(234 mg, 0.6 mmol) and ethylacetimidate hydrochloride (185 mg, 1.5 mmol) in EtOH (12 mL) was heatedat reflux for 0.5 h. The mixture was cooled and partitioned betweenethyl acetate and H2O. The organic layer was dried over Na2SO4 andevaporated in vacuum to give an amorphous residue (261 mg). A sample ofthis material (92 mg) was dissolved in a 33% solution (3 mL) ofmethylamine in EtOH. After being stirred for 0.5 h at 23° C., thereaction mixture was evaporated in vacuum and the residue was heated in1,4-dioxane (5 mL) to 100° C. for 2 h. The solvent was evaporated invacuum and the crude product was chromatographed on silica gel usingethyl acetate and ethyl acetate/methanol (4:1) as eluent. The purifiedproduct was triturated with ethyl acetate to give the title compound aslight yellow solid (26 mg).

MS (ISP) 426.4 (M+H)⁺; mp 238–240° C. (dec.).

Example 1673-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-N-hydroxy-benzamidine

To a stirred suspension of3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzonitrile(Example 57) (355 mg, 1 mmol) in EtOH (60 mL) was added at 23° C. over 6h 50% aqueous hydroxylamine solution (3.48 mL, 60 mmol) in 6 portions.The mixture was cooled in the ice-bath, diluted with H₂O (100 mL) andstirred for 1 h. The precipitate was collected by filtration, washedwith water and Et₂O, and triturated with ethyl acetate to give the titlecompound as light yellow solid (336 mg).

MS (ISP) 389.2 [(M+H)⁺]; mp 257–259° C. (dec.).

Example 1688-(4-Fluoro-phenyl)-4-{3-[5-(3-hydroxy-propyl)-[1,2,4]oxadiazol-3-yl]-phenyl}-1,3-dihydro-benzo[b][1,4]diazepin-2-one

To a stirred suspension of3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-N-hydroxy-benzamidine(Example 167) (78 mg, 0.2 mmol) in EtOH (3 mL) was added at 23° C.sodium hydride (55% dispersion in oil, 32 mg, 0.8 mmol) and the mixturewas stirred at 23° C. for 5 min. Butyrolactone (103 mg, 1.2 mmol) wasadded and the mixture was heated to 70° C. for 3 h. The reaction mixturewas cooled to 23° C. and partitioned between ethyl acetate and H₂O. Theorganic layer was dried over Na₂SO₄, evaporated in vacuum, and theresidue was crystallized from dichloromethane to give the title compoundas light yellow solid (60 mg).

MS (ISP) 457.3 [(M+H)⁺]; mp 220–222° C.

Example 1698-(4-Fluoro-phenyl)-4-[3-(3-methyl-[1,2,4]oxadiazol-5-yl)-phenyl]-1,3-dihydro-benzo[b][1,4]diazepin-2-one

To a solution of3-[7-(4-fluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-benzoicacid (Example 163) (262 mg, 0.7 mmol) and 1-hydroxybenzotriazole (130mg, 0.84 mmol) in CH₃CN/DMF (7 mL/10 mL), cooled to 0° C., was added EDC(161 mg, 0.84 mmol) and the mixture was stirred at 0° C. for 1 h.N-hydroxy-acetamidine (62 mg, 0.84 mmol) was added and stirring wascontinued for 4 h at 23° C. The reaction mixture was partitioned betweenethyl acetate and H₂O and the organic layer was dried over Na₂SO₄ andevaporated in vacuum. The residue was heated in toluene (30 mL) for 20 hat reflux. The mixture was cooled, evaporated in vacuum and the residuewas chromatographed on silica gel using ethyl acetate/hexane (2:1) aseluent. The purified product was triturated with ethyl acetate to givethe title compound as light yellow solid (49 mg). MS (ISN) 411.2[(M−H)⁻]; mp 266–268° C.

Example 1708-(4-Fluoro-phenyl)-4-(2-hydroxy-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

A mixture of 4′-fluoro-biphenyl-3,4-diamine (prepared from(3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester(Example G39) by treatment with TFA) (121 mg, 0.6 mmol) and4-hydroxycoumarin (97 mmol, 0.6 mmol) in xylene (8 mL) was heated to130° C. for 6 h. A yellow precipitate started to form after ca. 1 h. Themixture was cooled to 23° C., diluted with ethyl acetate (8 mL) andhexane (8 mL) and stirring was continued for 15 min. The precipitate wascollected by filtration and triturated with ethyl acetate/hexane (1:1)to give the title compound as a mixture with the isomeric7-(4-fluoro-phenyl)-4-(2-hydroxy-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-oneas yellow solid (117 mg).

MS (ISP) 347.3 [(M+H)⁺].

Example 1714-(3-Chloro-2,4-dihydroxy-phenyl)-8-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-one

By subjecting 4′-fluoro-biphenyl-3,4-diamine (prepared from(3-amino-4′-fluoro-biphenyl-4-yl)-carbamic acid tert.-butyl ester(Example G39) by treatment with TFA) (121 mg, 0.6 mmol) and8-chloro-4,8-dihydroxycoumarin (128 mmol, 0.6 mmol) in an analogousmanner to the procedure described in Example 170, the title compound wasobtained as a mixture with the isomeric4-(3-chloro-2,4-dihydroxy-phenyl)-7-(4-fluoro-phenyl)-1,3-dihydro-benzo[b][1,4]diazepin-2-oneas light yellow solid (103 mg).

MS (ISN) 395.1 [(M−H)⁻].

Example I

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 100 Powdered. lactose 95 White corn starch35 Polyvinylpyrrolidone 8 Na carboxymethylstarch 10 Magnesium stearate 2Tablet weight 250

Example II

Tablets of the following composition are produced in a conventionalmanner:

mg/Tablet Active ingredient 200 Powdered. lactose 100 White corn starch64 Polyvinylpyrrolidone 12 Na carboxymethylstarch 20 Magnesium stearate4 Tablet weight 400

Example III

Capsules of the following composition are produced:

mg/Capsule Active ingredient 50 Crystalline. lactose 60 Microcrystallinecellulose 34 Talc 5 Magnesium stearate 1 Capsule fill weight 150

The active ingredient having a suitable particle size, the crystallinelactose and the microcrystalline cellulose are homogeneously mixed withone another, sieved and thereafter talc and magnesium stearate areadmixed. The final mixture is filled into hard gelatin capsules ofsuitable size.

1. A compound of the formula:

wherein X is a single bond, R¹ is selected from the group consisting ofhydrogen, halogen, nitro, unsubstituted lower alkyl or lower alkylsubstituted by halogen, alkoxycarbonyl, unsubstituted lower cycloalkylor cycloalkyl substituted with oxygen, unsubstituted benzoyl or benzoylsubstituted with a substituent selected from the group consisting oflower alkyl, lower alkyl substituted by halogen and halogen,unsubstituted phenyl, phenyl substituted by a substituent selected fromthe group consisting of hydroxy, lower alkyl, lower alkyl substituted byhalogen, lower cycloalkyl, lower alkoxy, lower alkoxy substituted byhalogen and cyano, styrenyl, phenylethyl, napthyl, biphenyl,benzofuranyl, an unsubstituted 5- or 6-membered heterocyclic ring, a 5-or 6-membered heterocyclic ring substituted by a substituent selectedfrom the group consisting of oxo, benzoyl, methanesulfonyl,benzenesulfonyl and acetyl; and R³ is selected from the group consistingof unsubstituted pyridine, unsubstituted thienyl and unsubstitutedthiazolyl, or substituted pyridine, substituted thienyl and substitutedthiazolyl, said substituted pyridine, said substituted thiophenyl orsaid substituted thiazoyl being substituted by a substitutent selectedfrom the group consisting of halogen, cyano, nitro, azido, hydroxy,carboxy, morpholine-4-carbonyl, carbamoyl, thiocarbamoyl,N-hydroxycarbamoyl, trimethylsilyl-ethynyl, lower alkyl, lower alkynyl,lower alkoxy, halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl,lower alkylaminocarbonyl, or lower alkyl, lower alkynyl, lower alkoxy,halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, loweralkylaminocarbonyl substituted by a substitutent selected from the groupconsisting of amino, lower alkylamino, acylamino, oxo, hydroxy; loweralkoxy, lower alkylthio, unsubstituted carboxy, esterified and amidatedcarboxy, an unsubstituted 5-membered aromatic heterocycle, a 5-memberedaromatic heterocycle substituted by a substituent selected from thegroup consisting of amino, lower alkylamino, acylamino, oxo, hydroxy,lower alkoxy, lower alkylthio, carboxy, carboxy esterified with loweralkyl, carboxy amidated with lower alkylamino which is eventuallysubstituted by hydroxy, lower alkyl, lower alkyl substituted by asubstituent selected from the group consisting of halogen, hydroxy,amino, lower alkylamino, acylamino, amidino and amidino substituted by asubstituent selected from the group consisting of lower alkyl,—C(NRR′)═NR″ wherein R, R′ and R″ are hydrogen or lower alkyl, hydroxy,lower alkoxy, lower alkylthio, acyloxy, lower alkylsulfinyl, loweralkylsulfonyl, lower alkoxy-lower alkylsulfanyl, lower alkylsulfanyl,cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, lower alkoxyimino,lower alkoximino which is esterified or amidated, lower alkenyl, oxo,cyano, carbamoyloxy, sulfamoyl and sulfamoyl substituted by lower alkyl;and with the proviso that when X is a single bond and R³ is pyridinyl,R¹ is not hydrogen or methyl, or a pharmaceutically acceptable acidaddition salt thereof.
 2. The compound of formula I according to claim1, wherein R³ is selected from the group consisting of unsubstitutedthienyl, thienyl substituted with halogen or cyano, unsubstitutedpyridinyl and pyridinyl substituted with halogen or cyano.
 3. Thecompound of formula I according to claim 2, selected from the groupconsisting of2-[7-(4-Fluoro-phenyl)-4-oxo-4,5-dihydro-1H-benzo[b][1,4]diazepin-2-yl]-thiophene-3-carbonitrile,and4-[7-(2,4-Difluoro-phenyl)-4-oxo-4,5-dihydro-3H-benzo[b][1,4]diazepin-2-yl]-pyridine-2-carbonitrile.4. A pharmaceutical composition comprising a compound of formula 1

wherein X is a single bond, R¹ is selected from the group consisting ofhydrogen, halogen, nitro, unsubstituted lower alkyl or lower alkylsubstituted by halogen, alkoxycarbonyl, unsubstituted lower cycloalkylor cycloalkyl substituted with oxygen, unsubstituted benzoyl or benzoylsubstituted with a substituent selected from the group consisting oflower alkyl, lower alkyl substituted by halogen and halogen,unsubstituted phenyl, phenyl substituted by a substituent selected fromthe group consisting of hydroxy, lower alkyl, lower alkyl substituted byhalogen, lower cycloalkyl, lower alkoxy, lower alkoxy substituted byhalogen and cyano, styrenyl, phenylethyl, napthyl, biphenyl,benzofuranyl, an unsubstituted 5- or 6-membered heterocyclic ring, a 5-or 6-membered heterocyclic ring substituted by a substituent selectedfrom the group consisting of oxo, benzoyl, methanesulfonyl,benzenesulfonyl and acetyl; and R³ is selected from the group consistingof unsubstituted pyridine, unsubstituted thienyl and unsubstitutedthiazolyl, or substituted pyridine, substituted thienyl and substitutedthiazolyl, said substituted pyridine, said substituted thienyl or saidsubstituted thiazoyl being substituted by a substitutent selected fromthe group consisting of halogen, cyano, nitro, azido, hydroxy, carboxy,morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl,trimethylsilyl-ethynyl, lower alkyl, lower alkynyl, lower alkoxy,halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, loweralkylaminocarbonyl, or lower alkyl, lower alkynyl, lower alkoxy,halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, loweralkylaminocarbonyl substituted by a substitutent selected from the groupconsisting of amino, lower alkylamino, acylamino, oxo, hydroxy; loweralkoxy, lower alkylthio, unsubstituted carboxy, esterified and amidatedcarboxy, an unsubstituted 5-membered aromatic heterocycle, a 5-memberedaromatic heterocycle substituted by a substituent selected from thegroup consisting of amino, lower alkylamino, acylamino, oxo, hydroxy,lower alkoxy, lower alkylthio, carboxy, carboxy esterified with loweralkyl, carboxy amidated with lower alkylamino which is eventuallysubstituted by hydroxy, lower alkyl, lower alkyl substituted by asubstituent selected from the group consisting of halogen, hydroxy,amino, lower alkylamino, acylamino, amidino and amidino substituted by asubstituent selected from the group consisting of lower alkyl,—C(NRR′)═NR″ wherein R, R′ and R″ are hydrogen or lower alkyl, hydroxy,lower alkoxy, lower alkylthio, acyloxy, lower alkylsulfinyl, loweralkylsulfonyl, lower alkoxy-lower alkylsulfanyl, lower alkylsulfanyl,cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, lower alkoxyimino,lower alkoximino which is esterified or amidated, lower alkenyl, oxo,cyano, carbamoyloxy, sulfamoyl and sulfamoyl substituted by lower alkyl;and with the proviso that when X is a single bond and R³ is pyridinyl,R¹ is not hydrogen or methyl, and a pharmaceutically acceptableexcipient.
 5. A process for preparing a compound of formula 1

wherein X is a single bond, R¹ is selected from the group consisting ofhydrogen, halogen, nitro, unsubstituted lower alkyl or lower alkylsubstituted by halogen, alkoxycarbonyl, unsubstituted lower cycloalkylor cycloalkyl substituted with oxygen, unsubstituted benzoyl or benzoylsubstituted with a substituent selected from the group consisting oflower alkyl, lower alkyl substituted by halogen and halogen,unsubstituted phenyl, phenyl substituted by a substituent selected fromthe group consisting of hydroxy, lower alkyl, lower alkyl substituted byhalogen, lower cycloalkyl, lower alkoxy, lower alkoxy substituted byhalogen and cyano, styrenyl, phenylethyl, napthyl, biphenyl,benzofuranyl, an unsubstituted 5- or 6-membered heterocyclic ring, a 5-or 6-membered heterocyclic ring substituted by a substituent selectedfrom the group consisting of oxo, benzoyl, methanesulfonyl,benzenesulfonyl and acetyl; and R³ is selected from the group consistingof unsubstituted pyridine, unsubstituted thienyl and unsubstitutedthiazolyl, or substituted pyridine, substituted thienyl and substitutedthiazolyl, said substituted pyridine, said substituted thienyl or saidsubstituted thiazoyl being substituted by a substitutent selected fromthe group consisting of halogen, cyano, nitro, azido, hydroxy, carboxy,morpholine-4-carbonyl, carbamoyl, thiocarbamoyl, N-hydroxycarbamoyl,trimethylsilyl-ethynyl, lower alkyl, lower alkynyl, lower alkoxy,halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, loweralkylaminocarbonyl, or lower alkyl, lower alkynyl, lower alkoxy,halo-lower alkyl, 4-lower alkyl-piperazine-1-carbonyl, loweralkylaminocarbonyl substituted by a substitutent selected from the groupconsisting of amino, lower alkylamino, acylamino, oxo, hydroxy; loweralkoxy, lower alkylthio, unsubstituted carboxy, esterified and amidatedcarboxy, an unsubstituted 5-membered aromatic heterocycle, a 5-memberedaromatic heterocycle substituted by a substituent selected from thegroup consisting of amino, lower alkylamino, acylamino, oxo, hydroxy,lower alkoxy, lower alkylthio, carboxy, carboxy esterified with loweralkyl, carboxy amidated with lower alkylamino which is eventuallysubstituted by hydroxy, lower alkyl, lower alkyl substituted by asubstituent selected from the group consisting of halogen, hydroxy,amino, lower alkylamino, acylamino, amidino and amidino substituted by asubstituent selected from the group consisting of lower alkyl,—C(NRR′)═NR″ wherein R, R′ and R″ are hydrogen or lower alkyl, hydroxy,lower alkoxy, lower alkylthio, acyloxy, lower alkylsulfinyl, loweralkylsulfonyl, lower alkoxy-lower alkylsulfanyl, lower alkylsulfanyl,cycloalkylsulfinyl, cycloalkylsulfonyl, hydroxyimino, lower alkoxyimino,lower alkoximino which is esterified or amidated, lower alkenyl, oxo,cyano, carbamoyloxy, sulfamoyl and sulfamoyl substituted by lower alkyl;and with the proviso that when X is a single bond and R³ is pyridinyl,R¹ is not hydrogen or methyl, comprising reacting a compound of formulaIII:

with a compound of formula IV or Iva:

wherein R is ethyl or butyl, thereby yielding the compound of formula II

deprotecting of the amino group; and cyclizing, thereby forming acompound of formula I of claim 1.